Nina He1,2,3,4, Dun Yuan1, Minjie Luo1,2,3,4, Qing Xu1,2,3,4, Zhongchi Wen1,2,3,4, Ziqin Wang1,2,3,4, Jie Zhao1,2,3,4(), Ying Liu1,2,3,4()
. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China . Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, China . Sepsis Translational Medicine Key Lab of Hunan Province, Changsha 410008, China . National Medicine Functional Experimental Teaching Center, Changsha 410008, China
As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term “immunosuppression” refers to various factors that can directly harm immune cells’ structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.
SJ Dixon , KM Lemberg , MR Lamprecht , R Skouta , EM Zaitsev , CE Gleason , DN Patel , AJ Bauer , AM Cantley , WS Yang , B III Morrison , BR Stockwell . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060–1072 https://doi.org/10.1016/j.cell.2012.03.042
BR Stockwell , JPF Angeli , H Bayir , AI Bush , M Conrad , SJ Dixon , S Fulda , S Gascón , SK Hatzios , VE Kagan , K Noel , XJ Jiang , A Linkermann , ME Murphy , M Overholtzer , A Oyagi , GC Pagnussat , J Park , Q Ran , CS Rosenfeld , K Salnikow , DL Tang , FM Torti , SV Torti , S Toyokuni , KA Woerpel , DD Zhang . Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171(2): 273–285 https://doi.org/10.1016/j.cell.2017.09.021
4
E Nakamura , M Sato , HL Yang , F Miyagawa , M Harasaki , K Tomita , S Matsuoka , A Noma , K Iwai , N Minato . 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer. J Biol Chem 1999; 274(5): 3009–3016 https://doi.org/10.1074/jbc.274.5.3009
5
P Koppula , YL Zhang , L Zhuang , BY Gan . Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun 2018; 38(1): 12 https://doi.org/10.1186/s40880-018-0288-x
6
X Sun , Z Ou , R Chen , X Niu , D Chen , R Kang , D Tang . Activation of the p62-Keap1–NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 2016; 63(1): 173–184 https://doi.org/10.1002/hep.28251
7
M Conrad , H Sato . The oxidative stress-inducible cystine/glutamate antiporter, system xc−: cystine supplier and beyond. Amino Acids 2012; 42(1): 231–246 https://doi.org/10.1007/s00726-011-0867-5
8
WS Yang , R SriRamaratnam , ME Welsch , K Shimada , R Skouta , VS Viswanathan , JH Cheah , PA Clemons , AF Shamji , CB Clish , LM Brown , AW Girotti , VW Cornish , SL Schreiber , BR Stockwell . Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156(1–2): 317–331 https://doi.org/10.1016/j.cell.2013.12.010
9
BR Stockwell , JP Friedmann Angeli , H Bayir , AI Bush , M Conrad , SJ Dixon , S Fulda , S Gascon , SK Hatzios , VE Kagan , K Noel , X Jiang , A Linkermann , ME Murphy , M Overholtzer , A Oyagi , GC Pagnussat , J Park , Q Ran , CS Rosenfeld , K Salnikow , D Tang , FM Torti , SV Torti , S Toyokuni , KA Woerpel , DD Zhang . Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171(2): 273–285 https://doi.org/10.1016/j.cell.2017.09.021
10
L Galluzzi , I Vitale , SA Aaronson , JM Abrams , D Adam , P Agostinis , ES Alnemri , L Altucci , I Amelio , DW Andrews , M Annicchiarico-Petruzzelli , AV Antonov , E Arama , EH Baehrecke , NA Barlev , NG Bazan , F Bernassola , MJM Bertrand , K Bianchi , MV Blagosklonny , K Blomgren , C Borner , P Boya , C Brenner , M Campanella , E Candi , D Carmona-Gutierrez , F Cecconi , FK Chan , NS Chandel , EH Cheng , JE Chipuk , JA Cidlowski , A Ciechanover , GM Cohen , M Conrad , JR Cubillos-Ruiz , PE Czabotar , V D’Angiolella , TM Dawson , VL Dawson , Laurenzi V De , Maria R De , KM Debatin , RJ DeBerardinis , M Deshmukh , Daniele N Di , Virgilio F Di , VM Dixit , SJ Dixon , CS Duckett , BD Dynlacht , WS El-Deiry , JW Elrod , GM Fimia , S Fulda , AJ Garcia-Saez , AD Garg , C Garrido , E Gavathiotis , P Golstein , E Gottlieb , DR Green , LA Greene , H Gronemeyer , A Gross , G Hajnoczky , JM Hardwick , IS Harris , MO Hengartner , C Hetz , H Ichijo , M Jaattela , B Joseph , PJ Jost , PP Juin , WJ Kaiser , M Karin , T Kaufmann , O Kepp , A Kimchi , RN Kitsis , DJ Klionsky , RA Knight , S Kumar , SW Lee , JJ Lemasters , B Levine , A Linkermann , SA Lipton , RA Lockshin , C Lopez-Otin , SW Lowe , T Luedde , E Lugli , M MacFarlane , F Madeo , M Malewicz , W Malorni , G Manic , JC Marine , SJ Martin , JC Martinou , JP Medema , P Mehlen , P Meier , S Melino , EA Miao , JD Molkentin , UM Moll , C Munoz-Pinedo , S Nagata , G Nunez , A Oberst , M Oren , M Overholtzer , M Pagano , T Panaretakis , M Pasparakis , JM Penninger , DM Pereira , S Pervaiz , ME Peter , M Piacentini , P Pinton , JHM Prehn , H Puthalakath , GA Rabinovich , M Rehm , R Rizzuto , CMP Rodrigues , DC Rubinsztein , T Rudel , KM Ryan , E Sayan , L Scorrano , F Shao , Y Shi , J Silke , HU Simon , A Sistigu , BR Stockwell , A Strasser , G Szabadkai , SWG Tait , D Tang , N Tavernarakis , A Thorburn , Y Tsujimoto , B Turk , Berghe T Vanden , P Vandenabeele , Heiden MG Vander , A Villunger , HW Virgin , KH Vousden , D Vucic , EF Wagner , H Walczak , D Wallach , Y Wang , JA Wells , W Wood , J Yuan , Z Zakeri , B Zhivotovsky , L Zitvogel , G Melino , G Kroemer . Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018; 25(3): 486–541 https://doi.org/10.1038/s41418-017-0012-4
11
A Roveri , M Maiorino , F Ursini . Enzymatic and immunological measurements of soluble and membrane-bound phospholipid-hydroperoxide glutathione peroxidase. Methods Enzymol 1994; 233: 202–212 https://doi.org/10.1016/S0076-6879(94)33023-9
12
Y Liu , L Zhou , C Lv , L Liu , S Miao , Y Xu , K Li , Y Zhao , J Zhao . PGE2 pathway mediates oxidative stress-induced ferroptosis in renal tubular epithelial cells. FEBS J 2023; 290(2): 533–549 https://doi.org/10.1111/febs.16609
13
JPF Angeli , M Schneider , B Proneth , YY Tyurina , VA Tyurin , VJ Hammond , N Herbach , M Aichler , A Walch , E Eggenhofer , D Basavarajappa , O Rådmark , S Kobayashi , T Seibt , H Beck , F Neff , I Esposito , R Wanke , H Förster , O Yefremova , M Heinrichmeyer , GW Bornkamm , EK Geissler , SB Thomas , BR Stockwell , VB O’Donnell , VE Kagan , JA Schick , M Conrad . Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16(12): 1180–1191 https://doi.org/10.1038/ncb3064
14
SJ Wang , DW Li , Y Ou , L Jiang , Y Chen , YM Zhao , W Gu . Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep 2016; 17(2): 366–373 https://doi.org/10.1016/j.celrep.2016.09.022
15
T Luedde , N Kaplowitz , RF Schwabe . Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 2014; 147(4): 765–783.e4 https://doi.org/10.1053/j.gastro.2014.07.018
16
LJ Chen , WS Hambright , R Na , QT Ran . Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 2015; 290(47): 28097–28106 https://doi.org/10.1074/jbc.M115.680090
17
Van B Do , F Gouel , A Jonneaux , K Timmerman , P Gelé , M Pétrault , M Bastide , C Laloux , C Moreau , R Bordet , D Devos , JC Devedjian . Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis 2016; 94: 169–178 https://doi.org/10.1016/j.nbd.2016.05.011
18
Y Zhao , Y Liu , Y Xu , K Li , L Zhou , H Qiao , Q Xu , J Zhao . The role of ferroptosis in blood-brain barrier injury. Cell Mol Neurobiol 2023; 43(1): 223–236 https://doi.org/10.1007/s10571-022-01197-5
19
L Galluzzi , JM Bravo-San Pedro , G Kroemer . Ferroptosis in p53-dependent oncosuppression and organismal homeostasis. Cell Death Differ 2015; 22(8): 1237–1238 https://doi.org/10.1038/cdd.2015.54
20
N Guo . Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma. Transl Cancer Res 2022; 11(8): 2688–2699 https://doi.org/10.21037/tcr-21-2157
21
Y Yu , Y Yan , FL Niu , YJ Wang , XY Chen , GD Su , YR Liu , XL Zhao , L Qian , P Liu , YY Xiong . Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov 2021; 7: 193 https://doi.org/10.1038/s41420-021-00579-w
Y Cui , Y Zhang , XL Zhao , LM Shao , GP Liu , CJ Sun , R Xu , ZL Zhang . ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun 2021; 93: 312–321 https://doi.org/10.1016/j.bbi.2021.01.003
24
ZN Xiao , DM Shen , T Lan , C Wei , ZL Luo , W Chen , YR Zhang , CG Zhang , YM Wang , YB Lu , PP Wang , F Yang , Q Li , LY Hu , WH Wu . Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice. Redox Biol 2022; 50: 102256 https://doi.org/10.1016/j.redox.2022.102256
25
Y Xu , Y Liu , K Li , D Yuan , S Yang , L Zhou , Y Zhao , S Miao , C Lv , J Zhao . COX-2/PGE2 pathway inhibits the ferroptosis induced by cerebral ischemia reperfusion. Mol Neurobiol 2022; 59(3): 1619–1631 https://doi.org/10.1007/s12035-021-02706-1
26
Y Li , DC Feng , ZY Wang , Y Zhao , RM Sun , DH Tian , DS Liu , F Zhang , SL Ning , JH Yao , XF Tian . Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 2019; 26(11): 2284–2299 https://doi.org/10.1038/s41418-019-0299-4
27
YL Rong , J Fan , CY Ji , ZH Wang , XH Ge , JX Wang , W Ye , GY Yin , WH Cai , W Liu . USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1. Cell Death Differ 2022; 29(6): 1164–1175 https://doi.org/10.1038/s41418-021-00907-8
28
DP Del Re , D Amgalan , A Linkermann , QH Liu , RN Kitsis . Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev 2019; 99(4): 1765–1817 https://doi.org/10.1152/physrev.00022.2018
29
P Aisen , C Enns , M Wessling-Resnick . Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 2001; 33(10): 940–959 https://doi.org/10.1016/S1357-2725(01)00063-2
P Li , M Jiang , K Li , H Li , Y Zhou , X Xiao , Y Xu , S Krishfield , PE Lipsky , GC Tsokos , X Zhang . Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat Immunol 2021; 22(9): 1107–1117 https://doi.org/10.1038/s41590-021-00993-3
32
Y Ren , JL Tang , MY Mok , AWK Chan , A Wu , CS Lau . Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 2003; 48(10): 2888–2897 https://doi.org/10.1002/art.11237
33
T Rothe , F Gruber , S Uderhardt , N Ipseiz , S Rossner , O Oskolkova , S Bluml , N Leitinger , W Bicker , VN Bochkov , M Yamamoto , A Steinkasserer , G Schett , E Zinser , G Kronke . 12/15-lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. J Clin Invest 2015; 125(5): 1944–1954 https://doi.org/10.1172/JCI78490
34
E Dai , L Han , J Liu , Y Xie , G Kroemer , DJ Klionsky , HJ Zeh , R Kang , J Wang , D Tang . Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 2020; 16(11): 2069–2083 https://doi.org/10.1080/15548627.2020.1714209
35
EM Burton , J Voyer , BE Gewurz . Epstein-Barr virus latency programs dynamically sensitize B cells to ferroptosis. Proc Natl Acad Sci USA 2022; 119(11): e2118300119 https://doi.org/10.1073/pnas.2118300119
36
Y Zhao , Z Liu , G Liu , Y Zhang , S Liu , D Gan , W Chang , X Peng , ES Sung , K Gilbert , Y Zhu , X Wang , Z Zeng , H Baldwin , G Ren , J Weaver , A Huron , T Mayberry , Q Wang , Y Wang , ME Diaz-Rubio , X Su , MS Stack , S Zhang , X Lu , RD Sheldon , J Li , C Zhang , J Wan , X Lu . Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab 2023; 35(10): 1688–1703.e10 https://doi.org/10.1016/j.cmet.2023.09.004
37
SM Poznanski , K Singh , TM Ritchie , JA Aguiar , IY Fan , AL Portillo , EA Rojas , F Vahedi , A El-Sayes , S Xing , M Butcher , Y Lu , AC Doxey , JD Schertzer , HW Hirte , AA Ashkar . Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab 2021; 33(6): 1205–1220.e5 https://doi.org/10.1016/j.cmet.2021.03.023
PJ Murray , TA Wynn . Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011; 11(11): 723–737 https://doi.org/10.1038/nri3073
41
A Shapouri-Moghaddam , S Mohammadian , H Vazini , M Taghadosi , SA Esmaeili , F Mardani , B Seifi , A Mohammadi , JT Afshari , A Sahebkar . Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018; 233(9): 6425–6440 https://doi.org/10.1002/jcp.26429
VH Perry , J Teeling . Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 2013; 35(5): 601–612 https://doi.org/10.1007/s00281-013-0382-8
44
Y Lavin , A Mortha , A Rahman , M Merad . Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 2015; 15(12): 731–744 https://doi.org/10.1038/nri3920
45
N Yagoda , M von Rechenberg , E Zaganjor , AJ Bauer , WS Yang , DJ Fridman , AJ Wolpaw , I Smukste , JM Peltier , JJ Boniface , R Smith , SL Lessnick , S Sahasrabudhe , BR Stockwell . RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447(7146): 865–868 https://doi.org/10.1038/nature05859
46
SJ Dixon , KM Lemberg , MR Lamprecht , R Skouta , EM Zaitsev , CE Gleason , DN Patel , AJ Bauer , AM Cantley , WS Yang , B 3rd Morrison , BR Stockwell . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060–1072 https://doi.org/10.1016/j.cell.2012.03.042
47
Y Cui , ZL Zhang , X Zhou , ZY Zhao , R Zhao , XY Xu , XY Kong , JY Ren , XJ Yao , Q Wen , FF Guo , SL Gao , JD Sun , Q Wan . Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflammation 2021; 18(1): 249 https://doi.org/10.1186/s12974-021-02231-x
48
L Cassetta , JW Pollard . Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov 2018; 17(12): 887–904 https://doi.org/10.1038/nrd.2018.169
49
A Mantovani , T Schioppa , C Porta , P Allavena , A Sica . Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 2006; 25(3): 315–322 https://doi.org/10.1007/s10555-006-9001-7
50
A Sica , V Bronte . Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 2007; 117(5): 1155–1166 https://doi.org/10.1172/JCI31422
51
Y Xia , L Rao , H Yao , Z Wang , P Ning , X Chen . Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater 2020; 32(40): 2002054 https://doi.org/10.1002/adma.202002054
52
E Dai , L Han , J Liu , Y Xie , HJ Zeh , R Kang , L Bai , D Tang . Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun 2020; 11(1): 6339 https://doi.org/10.1038/s41467-020-20154-8
53
J Wu , Z Feng , L Chen , Y Li , HJ Bian , JJ Geng , ZH Zheng , XH Fu , Z Pei , YF Qin , L Yang , YL Zhao , K Wang , R Chen , Q He , G Nan , XJ Jiang , ZN Chen , P Zhu . TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat Commun 2022; 13(1): 676 https://doi.org/10.1038/s41467-021-27948-4
54
SM Ouyang , HX Li , LL Lou , QY Huang , ZH Zhang , JS Mo , M Li , JY Lu , K Zhu , YJ Chu , W Ding , JZ Zhu , ZY Lin , L Zhong , JJ Wang , PB Yue , J Turkson , PQ Liu , YX Wang , XL Zhang . Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol 2022; 52: 102317 https://doi.org/10.1016/j.redox.2022.102317
55
G Corna , L Campana , E Pignatti , A Castiglioni , E Tagliafico , L Bosurgi , A Campanella , S Brunelli , AA Manfredi , P Apostoli , L Silvestri , C Camaschella , P Rovere-Querini . Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 2010; 95(11): 1814–1822 https://doi.org/10.3324/haematol.2010.023879
56
S Recalcati , M Locati , A Marini , P Santambrogio , F Zaninotto , M De Pizzol , L Zammataro , D Girelli , G Cairo . Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 2010; 40(3): 824–835 https://doi.org/10.1002/eji.200939889
57
AA Kapralov , Q Yang , HH Dar , YY Tyurina , TS Anthonymuthu , R Kim , CM St Croix , K Mikulska-Ruminska , B Liu , IH Shrivastava , VA Tyurin , HC Ting , YL Wu , Y Gao , GV Shurin , MA Artyukhova , LA Ponomareva , PS Timashev , RM Domingues , DA Stoyanovsky , JS Greenberger , RK Mallampalli , I Bahar , DI Gabrilovich , H Bayir , VE Kagan . Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 2020; 16(3): 278–290 https://doi.org/10.1038/s41589-019-0462-8
58
A Kumar , KP Singh , P Bali , S Anwar , A Kaul , OP Singh , BK Gupta , N Kumari , MN Alam , M Raziuddin , MP Sinha , S Gourinath , AK Sharma , M Sohail . iNOS polymorphism modulates iNOS/NO expression via impaired antioxidant and ROS content in P. vivax and P. falciparum infection. Redox Biol 2018; 15: 192–206 https://doi.org/10.1016/j.redox.2017.12.005
59
ZL Cui , WK Li , YD Wang , MR Zhao , KL Liu , Y Yang , S Teng , N Zhang , L Min , P Li , ST Zhang , JX Xu , J Wu . M2 macrophage-derived exosomal ferritin heavy chain promotes colon cancer cell proliferation. Biol Trace Elem Res 2023; 201(8): 3717–3728 https://doi.org/10.1007/s12011-022-03488-w
60
K Kashfi , J Kannikal , N Nath . Macrophage reprogramming and cancer therapeutics: role of iNOS-derived NO. Cells 2021; 10(11): 3194 https://doi.org/10.3390/cells10113194
61
KM Giger , TA Kalfa . Phylogenetic and ontogenetic view of erythroblastic islands. BioMed Res Int 2015; 2015: 873628 https://doi.org/10.1155/2015/873628
62
MD Knutson , M Oukka , LM Koss , F Aydemir , M Wessling-Resnick . Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA 2005; 102(5): 1324–1328 https://doi.org/10.1073/pnas.0409409102
63
LA Youssef , A Rebbaa , S Pampou , SP Weisberg , BR Stockwell , EA Hod , SL Spitalnik . Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Blood 2018; 131(23): 2581–2593 https://doi.org/10.1182/blood-2017-12-822619
64
H Yuan , XM Li , XY Zhang , R Kang , DL Tang . Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 2016; 478(3): 1338–1343 https://doi.org/10.1016/j.bbrc.2016.08.124
65
SH Liu , ZS Gao , WQ He , YT Wu , JW Liu , S Zhang , LP Yan , SY Mao , XZ Shi , WT Fan , SQ Song . The gut microbiota metabolite glycochenodeoxycholate activates TFR-ACSL4-mediated ferroptosis to promote the development of environmental toxin-linked MAFLD. Free Radic Biol Med 2022; 193: 213–226 https://doi.org/10.1016/j.freeradbiomed.2022.10.270
66
L Gao , JS Zhang , TT Yang , L Jiang , XQ Liu , S Wang , X Wang , YB Huang , HY Wang , MY Zhang , TT Gong , LJ Ma , C Li , CY He , XM Meng , YG Wu . STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease. Mol Ther 2023; 31(10): 3084–3103 https://doi.org/10.1016/j.ymthe.2023.07.026
67
CY Niu , DM Jiang , YN Guo , ZL Wang , Q Sun , X Wang , WK Ling , XG An , CW Ji , S Li , H Zhao , B Kang . Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage. Life Sci 2023; 332: 122109 https://doi.org/10.1016/j.lfs.2023.122109
68
H Zheng , L Jiang , T Tsuduki , M Conrad , S Toyokuni . Embryonal erythropoiesis and aging exploit ferroptosis. Redox Biol 2021; 48: 102175 https://doi.org/10.1016/j.redox.2021.102175
69
ZY Wu , D Li , DY Tian , XJ Liu , ZM Wu . Aspirin mediates protection from diabetic kidney disease by inducing ferroptosis inhibition. PLoS One 2022; 17(12): e0279010 https://doi.org/10.1371/journal.pone.0279010
70
EP Amaral , DL Costa , S Namasivayam , N Riteau , O Kamenyeva , L Mittereder , KD Mayer-Barber , BB Andrade , A Sher . A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis. J Exp Med 2019; 216(3): 556–570 https://doi.org/10.1084/jem.20181776
71
DE Kennedy , KL Knight . Inhibition of B lymphopoiesis by adipocytes and IL-1-producing myeloid-derived suppressor cells. J Immunol 2015; 195(6): 2666–2674 https://doi.org/10.4049/jimmunol.1500957
72
SM Behar , M Divangahi , HG Remold . Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy. Nat Rev Microbiol 2010; 8(9): 668–674 https://doi.org/10.1038/nrmicro2387
73
HH Dar , YY Tyurina , K Mikulska-Ruminska , I Shrivastava , HC Ting , VA Tyurin , J Krieger , CM St Croix , S Watkins , E Bayir , G Mao , CR Armbruster , A Kapralov , H Wang , MR Parsek , TS Anthonymuthu , AF Ogunsola , BA Flitter , CJ Freedman , JR Gaston , TR Holman , JM Pilewski , JS Greenberger , RK Mallampalli , Y Doi , JS Lee , I Bahar , JM Bomberger , H Bayir , VE Kagan . Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium. J Clin Invest 2018; 128(10): 4639–4653 https://doi.org/10.1172/JCI99490
74
X Luo , HB Gong , HY Gao , YP Wu , WY Sun , ZQ Li , G Wang , B Liu , L Liang , H Kurihara , WJ Duan , YF Li , RR He . Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2. Cell Death Differ 2021; 28(6): 1971–1989 https://doi.org/10.1038/s41418-020-00719-2
75
Y Cui , Z Zhang , X Zhou , Z Zhao , R Zhao , X Xu , X Kong , J Ren , X Yao , Q Wen , F Guo , S Gao , J Sun , Q Wan . Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflammation 2021; 18(1): 249 https://doi.org/10.1186/s12974-021-02231-x
76
C Summers , SM Rankin , AM Condliffe , N Singh , AM Peters , ER Chilvers . Neutrophil kinetics in health and disease. Trends Immunol 2010; 31(8): 318–324 https://doi.org/10.1016/j.it.2010.05.006
77
RS Hotchkiss , LL Moldawer , SM Opal , K Reinhart , IR Turnbull , JL Vincent . Sepsis and septic shock. Nat Rev Dis Primers 2016; 2(1): 16045 https://doi.org/10.1038/nrdp.2016.45
W Cai , T Yang , H Liu , LJ Han , K Zhang , XM Hu , XJ Zhang , KJ Yin , YQ Gao , MVL Bennett , RK Leak , J Chen . Peroxisome proliferator-activated receptor γ (PPARγ): a master gatekeeper in CNS injury and repair. Prog Neurobiol 2018; 163–164: 27–58 https://doi.org/10.1016/j.pneurobio.2017.10.002
80
D Zhao , C Xue , Y Yang , J Li , X Wang , Y Chen , S Zhang , Y Chen , Y Duan , X Yang , J Han . Lack of Nogo-B expression ameliorates PPARγ deficiency-aggravated liver fibrosis by regulating TLR4-NF-κB-TNF-α axis and macrophage polarization. Biomed Pharmacother 2022; 153: 113444 https://doi.org/10.1016/j.biopha.2022.113444
81
X Xue , T Dai , J Chen , Y Xu , Z Yang , J Huang , W Xu , S Li , Q Meng . PPARγ activation suppresses chondrocyte ferroptosis through mitophagy in osteoarthritis. J Orthop Surg Res 2023; 18(1): 620 https://doi.org/10.1186/s13018-023-04092-x
82
ML Kruzel , M Zimecki , JK Actor . Lactoferrin in a context of inflammation-induced pathology. Front Immunol 2017; 8: 1438 https://doi.org/10.3389/fimmu.2017.01438
83
B Wang , YP Timilsena , E Blanch , B Adhikari . Lactoferrin: structure, function, denaturation and digestion. Crit Rev Food Sci Nutr 2019; 59(4): 580–596 https://doi.org/10.1080/10408398.2017.1381583
GS Gullotta , Feo D De , E Friebel , A Semerano , GM Scotti , A Bergamaschi , E Butti , E Brambilla , A Genchi , A Capotondo , M Gallizioli , S Coviello , M Piccoli , T Vigo , Valle P Della , P Ronchi , G Comi , A D’Angelo , N Maugeri , L Roveri , A Uccelli , B Becher , G Martino , M Bacigaluppi . Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. Nat Immunol 2023; 24(6): 925–940 https://doi.org/10.1038/s41590-023-01505-1
86
LY Wei , C Liu , J Wang , X Zheng , Q Peng , QR Ye , ZL Qin , ZS Li , XY Zhang , YG Wu , YQ Wen , XM Zhang , Q Yan , J Ma . Lactoferrin is required for early B cell development in C57BL/6 mice. J Hematol Oncol 2021; 14(1): 58 https://doi.org/10.1186/s13045-021-01074-6
W Li , G Feng , JM Gauthier , I Lokshina , R Higashikubo , S Evans , X Liu , A Hassan , S Tanaka , M Cicka , HM Hsiao , D Ruiz-Perez , A Bredemeyer , RW Gross , DL Mann , YY Tyurina , AE Gelman , VE Kagan , A Linkermann , KJ Lavine , D Kreisel . Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation. J Clin Invest 2019; 129(6): 2293–2304 https://doi.org/10.1172/JCI126428
89
F Ito , K Kato , I Yanatori , T Murohara , S Toyokuni . Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. Redox Biol 2021; 47: 102174 https://doi.org/10.1016/j.redox.2021.102174
90
KM Murphy , SL Reiner . The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2(12): 933–944 https://doi.org/10.1038/nri954
TR Mosmann , H Cherwinski , MW Bond , MA Giedlin , RL Coffman . Pillars article: two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 2005; 175(1): 5–14
93
H Park , ZX Li , XO Yang , SH Chang , R Nurieva , YH Wang , Y Wang , L Hood , Z Zhu , Q Tian , C Dong . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6(11): 1133–1141 https://doi.org/10.1038/ni1261
94
EV Acosta-Rodriguez , L Rivino , J Geginat , D Jarrossay , M Gattorno , A Lanzavecchia , F Sallusto , G Napolitani . Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8(6): 639–646 https://doi.org/10.1038/ni1467
J Shaw , A Chakraborty , A Nag , A Chattopadyay , AK Dasgupta , M Bhattacharyya . Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients. Eur J Haematol 2017; 99(5): 399–408 https://doi.org/10.1111/ejh.12936
97
Z Wang , W Yin , L Zhu , J Li , Y Yao , F Chen , M Sun , J Zhang , N Shen , Y Song , X Chang . Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity 2018; 49(1): 80–92.e7 https://doi.org/10.1016/j.immuni.2018.05.008
98
H Matsushita , A Hosoi , S Ueha , J Abe , N Fujieda , M Tomura , R Maekawa , K Matsushima , O Ohara , K Kakimi . Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNγ-dependent cell-cycle arrest. Cancer Immunol Res 2015; 3(1): 26–36 https://doi.org/10.1158/2326-6066.CIR-14-0098
99
TT Wei , MY Zhang , XH Zheng , TH Xie , W Wang , J Zou , Y Li , HY Li , J Cai , X Wang , J Tan , X Yang , Y Yao , L Zhu . Interferon-γ induces retinal pigment epithelial cell ferroptosis by a JAK1-2/STAT1/SLC7A11 signaling pathway in age-related macular degeneration. FEBS J 2022; 289(7): 1968–1983 https://doi.org/10.1111/febs.16272
100
T Cao , J Zhou , Q Liu , T Mao , B Chen , Q Wu , L Wang , JL Pathak , N Watanabe , J Li . Interferon-γ induces salivary gland epithelial cell ferroptosis in Sjogren’s syndrome via JAK/STAT1-mediated inhibition of system Xc. Free Radic Biol Med 2023; 205: 116–128 https://doi.org/10.1016/j.freeradbiomed.2023.05.027
101
K Kang , SH Park , J Chen , Y Qiao , E Giannopoulou , K Berg , A Hanidu , J Li , G Nabozny , K Kang , KH Park-Min , LB Ivashkiv . Interferon-γ represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF. Immunity 2017; 47(2): 235–250.e4 https://doi.org/10.1016/j.immuni.2017.07.017
102
X Ma , L Xiao , L Liu , L Ye , P Su , E Bi , Q Wang , M Yang , J Qian , Q Yi . CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab 2021; 33(5): 1001–1012.e5 https://doi.org/10.1016/j.cmet.2021.02.015
103
S Xu , O Chaudhary , P Rodriguez-Morales , X Sun , D Chen , R Zappasodi , Z Xu , AFM Pinto , A Williams , I Schulze , Y Farsakoglu , SK Varanasi , JS Low , W Tang , H Wang , B McDonald , V Tripple , M Downes , RM Evans , NA Abumrad , T Merghoub , JD Wolchok , MN Shokhirev , PC Ho , JL Witztum , B Emu , G Cui , SM Kaech . Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 2021; 54(7): 1561–1577.e7 https://doi.org/10.1016/j.immuni.2021.05.003
104
P Jiang , SQ Gu , D Pan , JX Fu , A Sahu , XH Hu , ZY Li , N Traugh , X Bu , B Li , J Liu , GJ Freeman , MA Brown , KW Wucherpfennig , XLS Liu . Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response. Cancer Immunol Res 2019; 7(2): B077 https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B077
105
MQ Hao , YX Jiang , Y Zhang , XY Yang , JH Han . Ferroptosis regulation by methylation in cancer. Bba-Rev Cancer 2023; 1878(6): 188972 https://doi.org/10.1016/j.bbcan.2023.188972
106
S Li , Y Huang . Ferroptosis: an iron-dependent cell death form linking metabolism, diseases, immune cell and targeted therapy. Clin Transl Oncol 2022; 24(1): 1–12 https://doi.org/10.1007/s12094-021-02669-8
107
D Wang , L Fu , H Sun , L Guo , RN DuBois . Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology 2015; 149(7): 1884–1895e https://doi.org/10.1053/j.gastro.2015.07.064
108
N Caronni , F La Terza , FM Vittoria , G Barbiera , L Mezzanzanica , V Cuzzola , S Barresi , M Pellegatta , P Canevazzi , G Dunsmore , C Leonardi , E Montaldo , E Lusito , E Dugnani , A Citro , MSF Ng , M Schiavo Lena , D Drago , A Andolfo , S Brugiapaglia , A Scagliotti , A Mortellaro , V Corbo , Z Liu , A Mondino , P Dellabona , L Piemonti , C Taveggia , C Doglioni , P Cappello , F Novelli , M Iannacone , LG Ng , F Ginhoux , S Crippa , M Falconi , C Bonini , L Naldini , M Genua , R Ostuni . IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer. Nature 2023; 623(7986): 415–422 https://doi.org/10.1038/s41586-023-06685-2
109
B Piqueras , J Connolly , H Freitas , AK Palucka , J Banchereau . Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors. Blood 2006; 107(7): 2613–2618 https://doi.org/10.1182/blood-2005-07-2965
X Zhou , L Zou , H Liao , J Luo , T Yang , J Wu , W Chen , K Wu , S Cen , D Lv , F Shu , Y Yang , C Li , B Li , X Mao . Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer. Acta Pharm Sin B 2022; 12(2): 692–707 https://doi.org/10.1016/j.apsb.2021.07.016
112
VR Juneja , KA McGuire , RT Manguso , MW LaFleur , N Collins , WN Haining , GJ Freeman , AH Sharpe . PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017; 214(4): 895–904 https://doi.org/10.1084/jem.20160801
113
JM Drijvers , JE Gillis , T Muijlwijk , TH Nguyen , EF Gaudiano , IS Harris , MW LaFleur , AE Ringel , CH Yao , K Kurmi , VR Juneja , JD Trombley , MC Haigis , AH Sharpe . Pharmacologic screening identifies metabolic vulnerabilities of CD8+ T Cells. Cancer Immunol Res 2021; 9(2): 184–199 https://doi.org/10.1158/2326-6066.CIR-20-0384
114
C Xu , S Sun , T Johnson , R Qi , S Zhang , J Zhang , K Yang . The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep 2021; 35(11): 109235 https://doi.org/10.1016/j.celrep.2021.109235
115
HP Wang , F Franco , YC Tsui , X Xie , MP Trefny , R Zappasodi , SR Mohmood , J Fernández-García , CH Tsai , I Schulze , F Picard , E Meylan , R Silverstein , I Goldberg , SM Fendt , JD Wolchok , T Merghoub , C Jandus , A Zippelius , PC Ho . CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 2020; 21(3): 298–308 https://doi.org/10.1038/s41590-019-0589-5
116
A Sharabi , GC Tsokos . T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat Rev Rheumatol 2020; 16(2): 100–112 https://doi.org/10.1038/s41584-019-0356-x
117
RD Michalek , VA Gerriets , SR Jacobs , AN Macintyre , NJ MacIver , EF Mason , SA Sullivan , AG Nichols , JC Rathmell . Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186(6): 3299–3303 https://doi.org/10.4049/jimmunol.1003613
118
F Hao , M Tian , X Zhang , X Jin , Y Jiang , X Sun , Y Wang , P Peng , J Liu , C Xia , Y Feng , M Wei . Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation. Proc Natl Acad Sci USA 2021; 118(22): e2014681118 https://doi.org/10.1073/pnas.2014681118
119
EA Tivol , F Borriello , AN Schweitzer , WP Lynch , JA Bluestone , AH Sharpe . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3(5): 541–547 https://doi.org/10.1016/1074-7613(95)90125-6
120
M Berg , N Zavazava . Regulation of CD28 expression on CD8 T cells by CTLA-4. J Leukoc Biol 2008; 83(4): 853–863 https://doi.org/10.1189/jlb.0107065
121
K Wing , Y Onishi , P Prieto-Martin , T Yamaguchi , M Miyara , Z Fehervari , T Nomura , S Sakaguchi . CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322(5899): 271–275 https://doi.org/10.1126/science.1160062
122
AL Mellor , DH Munn . IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4(10): 762–774 https://doi.org/10.1038/nri1457
123
M Tekguc , JB Wing , M Osaki , J Long , S Sakaguchi . Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc Natl Acad Sci USA 2021; 118(30): e2023739118 https://doi.org/10.1073/pnas.2023739118
124
LSK Walker . EFIS Lecture: understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunol Lett 2017; 184: 43–50 https://doi.org/10.1016/j.imlet.2017.02.007
125
P Sharma , S Goswami , D Raychaudhuri , BA Siddiqui , P Singh , A Nagarajan , J Liu , SK Subudhi , C Poon , KL Gant , SM Herbrich , S Anandhan , S Islam , M Amit , G Anandappa , JP Allison . Immune checkpoint therapy-current perspectives and future directions. Cell 2023; 186(8): 1652–1669 https://doi.org/10.1016/j.cell.2023.03.006
126
JH Xu , X Wu , XY Wang . Ferroptosis-related genes with regard to CTLA-4 and immune infiltration in hepatocellular carcinoma. Biochem Genet 2023; 61(2): 687–703 https://doi.org/10.1007/s10528-022-10279-4
127
D Yu , S Rao , LM Tsai , SK Lee , Y He , EL Sutcliffe , M Srivastava , M Linterman , L Zheng , N Simpson , JI Ellyard , IA Parish , CS Ma , QJ Li , CR Parish , CR Mackay , CG Vinuesa . The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009; 31(3): 457–468 https://doi.org/10.1016/j.immuni.2009.07.002
128
SK Lee , RJ Rigby , D Zotos , LM Tsai , S Kawamoto , JL Marshall , RR Ramiscal , TD Chan , D Gatto , R Brink , D Yu , S Fagarasan , DM Tarlinton , AF Cunningham , CG Vinuesa . B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med 2011; 208(7): 1377–1388 https://doi.org/10.1084/jem.20102065
129
U Klein , R Dalla-Favera . Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8(1): 22–33 https://doi.org/10.1038/nri2217
130
Y Yao , Z Chen , H Zhang , C Chen , M Zeng , J Yunis , Y Wei , Y Wan , N Wang , M Zhou , C Qiu , Q Zeng , HS Ong , H Wang , FV Makota , Y Yang , Z Yang , N Wang , J Deng , C Shen , Y Xia , L Yuan , Z Lian , Y Deng , C Guo , A Huang , P Zhou , H Shi , W Zhang , H Yi , D Li , M Xia , J Fu , N Wu , JB de Haan , N Shen , W Zhang , Z Liu , D Yu . Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol 2021; 22(9): 1127–1139 https://doi.org/10.1038/s41590-021-00996-0
131
D Mougiakakos , CC Johansson , R Jitschin , M Bottcher , R Kiessling . Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood 2011; 117(3): 857–861 https://doi.org/10.1182/blood-2010-09-307041
132
GJ van der Windt , B Everts , CH Chang , JD Curtis , TC Freitas , E Amiel , EJ Pearce , EL Pearce . Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012; 36(1): 68–78 https://doi.org/10.1016/j.immuni.2011.12.007
ML Maia , CS Pereira , G Melo , I Pinheiro , MA Exley , G Porto , MF Macedo . Invariant natural killer T cells are reduced in hereditary hemochromatosis patients. J Clin Immunol 2015; 35(1): 68–74 https://doi.org/10.1007/s10875-014-0118-0
N Baumgarth . The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 2011; 11(1): 34–46 https://doi.org/10.1038/nri2901
MC Hsu , KM Toellner , CG Vinuesa , ICM MacLennan . B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses. Proc Natl Acad Sci USA 2006; 103(15): 5905–5910 https://doi.org/10.1073/pnas.0601502103
139
VD Dang , E Hilgenberg , S Ries , P Shen , S Fillatreau . From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets. Curr Opin Immunol 2014; 28: 77–83 https://doi.org/10.1016/j.coi.2014.02.009
140
M Shapiro-Shelef , K Calame . Regulation of plasma-cell development. Nat Rev Immunol 2005; 5(3): 230–242 https://doi.org/10.1038/nri1572
141
AE Gilbert , P Karagiannis , T Dodev , A Koers , K Lacy , DH Josephs , P Takhar , JL Geh , C Healy , M Harries , KM Acland , SM Rudman , RL Beavil , PJ Blower , AJ Beavil , HJ Gould , J Spicer , FO Nestle , SN Karagiannis . Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies. PLoS One 2011; 6(4): e19330 https://doi.org/10.1371/journal.pone.0019330
142
J Kurai , H Chikumi , K Hashimoto , K Yamaguchi , A Yamasaki , T Sako , H Touge , H Makino , M Takata , M Miyata , M Nakamoto , N Burioka , E Shimizu . Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007; 13(5): 1552–1561 https://doi.org/10.1158/1078-0432.CCR-06-1726
143
JY Shi , Q Gao , ZC Wang , J Zhou , XY Wang , ZH Min , YH Shi , GM Shi , ZB Ding , AW Ke , Z Dai , SJ Qiu , K Song , J Fan . Margin-infiltrating CD20+ B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin Cancer Res 2013; 19(21): 5994–6005 https://doi.org/10.1158/1078-0432.CCR-12-3497
144
C Mlynarczyk , M Teater , J Pae , CR Chin , L Wang , T Arulraj , D Barisic , A Papin , KB Hoehn , E Kots , J Ersching , A Bandyopadhyay , E Barin , HX Poh , CM Evans , A Chadburn , Z Chen , H Shen , HM Isles , B Pelzer , I Tsialta , AS Doane , H Geng , MH Rehman , J Melnick , W Morgan , DTT Nguyen , O Elemento , MG Kharas , SR Jaffrey , DW Scott , G Khelashvili , M Meyer-Hermann , GD Victora , A Melnick . BTG1 mutation yields supercompetitive B cells primed for malignant transformation. Science 2023; 379(6629): eabj7412 https://doi.org/10.1126/science.abj7412
145
IJ Cho , D Kim , EO Kim , KH Jegal , JK Kim , SM Park , R Zhao , SH Ki , SC Kim , SK Ku . Cystine and methionine deficiency promotes ferroptosis by inducing B-cell translocation gene 1. Antioxidants 2021; 10(10): 1543 https://doi.org/10.3390/antiox10101543
J Han , SH Back , J Hur , YH Lin , R Gildersleeve , J Shan , CL Yuan , D Krokowski , S Wang , M Hatzoglou , MS Kilberg , MA Sartor , RJ Kaufman . ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 2013; 15(5): 481–490 https://doi.org/10.1038/ncb2738
148
L Yuniati , LT van der Meer , E Tijchon , DV Schenau , L van Emst , M Levers , SAL Palit , C Rodenbach , G Poelmans , PM Hoogerbrugge , JX Shan , MS Kilberg , B Scheijen , FN van Leeuwen . Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress. Oncotarget 2016; 7(3): 3128–3143 https://doi.org/10.18632/oncotarget.6519
149
W Zhang , J Wang , Z Liu , L Zhang , J Jing , L Han , A Gao . Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis. Free Radic Biol Med 2022; 193(Pt 1): 122–133 https://doi.org/10.1016/j.freeradbiomed.2022.10.273
150
AJ Clarke , T Riffelmacher , D Braas , RJ Cornall , AK Simon . B1a B cells require autophagy for metabolic homeostasis and self-renewal. J Exp Med 2018; 215(2): 399–413 https://doi.org/10.1084/jem.20170771
151
J Muri , H Thut , GW Bornkamm , M Kopf . B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep 2019; 29(9): 2731–2744.e4 https://doi.org/10.1016/j.celrep.2019.10.070
152
E Vivier , E Tomasello , M Baratin , T Walzer , S Ugolini . Functions of natural killer cells. Nat Immunol 2008; 9(5): 503–510 https://doi.org/10.1038/ni1582
153
LN Bodduluru , ER Kasala , RMR Madhana , CS Sriram . Natural killer cells: the journey from puzzles in biology to treatment of cancer. Cancer Lett 2015; 357(2): 454–467 https://doi.org/10.1016/j.canlet.2014.12.020
A Jewett , J Kos , Y Fong , MW Ko , T Safaei , M Perisic Nanut , K Kaur . NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis. Semin Cancer Biol 2018; 53: 178–188 https://doi.org/10.1016/j.semcancer.2018.08.001
B Cózar , M Greppi , S Carpentier , E Narni-Mancinelli , L Chiossone , E Vivier . Tumor-infiltrating natural killer cells. Cancer Discov 2021; 11(1): 34–44 https://doi.org/10.1158/2159-8290.CD-20-0655
159
SQ Crome , LT Nguyen , S Lopez-Verges , SYC Yang , B Martin , JY Yam , DJ Johnson , J Nie , M Pniak , PH Yen , A Milea , R Sowamber , SR Katz , MQ Bernardini , BA Clarke , PA Shaw , PA Lang , HK Berman , TJ Pugh , LL Lanier , PS Ohashi . A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 2017; 23(3): 368–375 https://doi.org/10.1038/nm.4278
160
A Bruno , C Focaccetti , A Pagani , AS Imperatori , M Spagnoletti , N Rotolo , AR Cantelmo , F Franzi , C Capella , G Ferlazzo , L Mortara , A Albini , DM Noonan . The Proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia 2013; 15(2): 133–142 https://doi.org/10.1593/neo.121758
161
I Levi , H Amsalem , A Nissan , M Darash-Yahana , T Peretz , O Mandelboim , J Rachmilewitz . Characterization of tumor infiltrating natural killer cell subset. Oncotarget 2015; 6(15): 13835–13843 https://doi.org/10.18632/oncotarget.3453
JP Böttcher , E Bonavita , P Chakravarty , H Blees , M Cabeza-Cabrerizo , S Sammicheli , NC Rogers , E Sahai , S Zelenay , e Sousa C Reis . NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 2018; 172(5): 1022–1037.e14 https://doi.org/10.1016/j.cell.2018.01.004
164
L Yao , J Hou , X Wu , Y Lu , Z Jin , Z Yu , B Yu , J Li , Z Yang , C Li , M Yan , Z Zhu , B Liu , C Yan , L Su . Cancer-associated fibroblasts impair the cytotoxic function of NK cells in gastric cancer by inducing ferroptosis via iron regulation. Redox Biol 2023; 67: 102923 https://doi.org/10.1016/j.redox.2023.102923
165
Merad M. , Sathe P. , Helft J. , Miller J. , Mortha A. . The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013; 31: 563–604 https://doi.org/10.1146/annurev-immunol-020711-074950
166
SE Henrickson , M Perro , SM Loughhead , B Senman , S Stutte , M Quigley , G Alexe , M Iannacone , MP Flynn , S Omid , JL Jesneck , S Imam , TR Mempel , IB Mazo , WN Haining , UH von Andrian . Antigen availability determines CD8+ T cell-dendritic cell interaction kinetics and memory fate decisions. Immunity 2013; 39(3): 496–507 https://doi.org/10.1016/j.immuni.2013.08.034
JR Cubillos-Ruiz , PC Silberman , MR Rutkowski , S Chopra , A Perales-Puchalt , M Song , S Zhang , SE Bettigole , D Gupta , K Holcomb , LH Ellenson , T Caputo , AH Lee , JR Conejo-Garcia , LH Glimcher . ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 2015; 161(7): 1527–1538 https://doi.org/10.1016/j.cell.2015.05.025
169
PF Liu , YT Feng , HW Li , X Chen , GS Wang , SY Xu , YL Li , L Zhao . Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell Mol Biol Lett 2020; 25(1): 10 https://doi.org/10.1186/s11658-020-00205-0
170
X Chen , J Huang , CH Yu , J Liu , WL Gao , JB Li , XX Song , ZA Zhou , CF Li , YC Xie , G Kroemer , JB Liu , DL Tang , R Kang . A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat Commun 2022; 13(1): 6318 https://doi.org/10.1038/s41467-022-34096-w
171
I Efimova , E Catanzaro , L Van der Meeren , VD Turubanova , H Hammad , TA Mishchenko , MV Vedunova , C Fimognari , C Bachert , F Coppieters , S Lefever , AG Skirtach , O Krysko , DV Krysko . Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J Immunother Cancer 2020; 8(2): e001369 https://doi.org/10.1136/jitc-2020-001369
172
R Förster , A Schubel , D Breitfeld , E Kremmer , I Renner-Muller , E Wolf , M Lipp . CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999; 99(1): 23–33 https://doi.org/10.1016/S0092-8674(00)80059-8
173
B Wiernicki , S Maschalidi , J Pinney , S Adjemian , T Vanden Berghe , KS Ravichandran , P Vandenabeele . Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity. Nat Commun 2022; 13(1): 3676 https://doi.org/10.1038/s41467-022-31218-2
174
HF Yan , T Zou , QZ Tuo , S Xu , H Li , AA Belaidi , P Lei . Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 2021; 6(1): 49 https://doi.org/10.1038/s41392-020-00428-9
175
H Zhu , A Santo , Z Jia , Y Li . GPx4 in bacterial infection and polymicrobial sepsis: involvement of ferroptosis and pyroptosis. Reactive Oxygen Species 2019; 7(21): 154–160 https://doi.org/10.20455/ros.2019.835
176
I Park , M Kim , K Choe , E Song , H Seo , Y Hwang , J Ahn , SH Lee , JH Lee , YH Jo , K Kim , GY Koh , P Kim . Neutrophils disturb pulmonary microcirculation in sepsis-induced acute lung injury. Eur Respir J 2019; 53(3): 1800786 https://doi.org/10.1183/13993003.00786-2018
177
E Pastille , S Didovic , D Brauckmann , M Rani , H Agrawal , FU Schade , Y Zhang , SB Flohé . Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J Immunol 2011; 186(2): 977–986 https://doi.org/10.4049/jimmunol.1001147
178
SE Wenzel , YY Tyurina , J Zhao , CM St Croix , HH Dar , G Mao , VA Tyurin , TS Anthonymuthu , AA Kapralov , AA Amoscato , K Mikulska-Ruminska , IH Shrivastava , EM Kenny , Q Yang , JC Rosenbaum , LJ Sparvero , DR Emlet , X Wen , Y Minami , F Qu , SC Watkins , TR Holman , AP VanDemark , JA Kellum , I Bahar , H Bayir , VE Kagan . PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 2017; 171(3): 628–641.e26 https://doi.org/10.1016/j.cell.2017.09.044
179
Y Liu , Y Zhao , K Li , S Miao , Y Xu , J Zhao . WD-40 repeat protein 26 protects against oxidative stress-induced injury in astrocytes via Nrf2/HO-1 pathways. Mol Biol Rep 2022; 49(2): 1045–1056 https://doi.org/10.1007/s11033-021-06925-6
180
HL Hu , YQ Chen , LL Jing , CL Zhai , L Shen . The link between ferroptosis and cardiovascular diseases: a novel target for treatment. Front Cardiovasc Med 2021; 8: 710963 https://doi.org/10.3389/fcvm.2021.710963
181
T Bai , MX Li , YF Liu , ZT Qiao , ZW Wang . Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med 2020; 160: 92–102 https://doi.org/10.1016/j.freeradbiomed.2020.07.026
182
YQ Zhou , HX Zhou , L Hua , C Hou , QW Jia , JX Chen , S Zhang , YJ Wang , S He , EZ Jia . Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis. Free Radic Biol Med 2021; 171: 55–68 https://doi.org/10.1016/j.freeradbiomed.2021.05.009
183
X Lin , SK Shan , F Xu , JY Zhong , F Wu , JY Duan , B Guo , FXZ Li , Y Wang , MH Zheng , QS Xu , LM Lei , WL Ou-Yang , YY Wu , KX Tang , MHE Ullah , XB Liao , LQ Yuan . The crosstalk between endothelial cells and vascular smooth muscle cells aggravates high phosphorus-induced arterial calcification. Cell Death Dis 2022; 13(7): 650 https://doi.org/10.1038/s41419-022-05064-5
184
A Broder , JJ Chan , C Putterman . Dendritic cells: an important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases. Clin Immunol 2013; 146(3): 197–206 https://doi.org/10.1016/j.clim.2012.12.002
185
JE Talmadge , DI Gabrilovich . History of myeloid-derived suppressor cells. Nat Rev Cancer 2013; 13(10): 739–752 https://doi.org/10.1038/nrc3581
186
KR Jordan , P Kapoor , E Spongberg , RP Tobin , DX Gao , VF Borges , MD McCarter . Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients. Cancer Immunol Immunother 2017; 66(4): 503–513 https://doi.org/10.1007/s00262-016-1953-z
187
T Condamine , DI Gabrilovich . Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32(1): 19–25 https://doi.org/10.1016/j.it.2010.10.002
188
A Trigunaite , A Khan , E Der , A Song , S Varikuti , TN Jorgensen . Gr-1(high) CD11b+ cells suppress B cell differentiation and lupus-like disease in lupus-prone male mice. Arthritis Rheum 2013; 65(9): 2392–2402 https://doi.org/10.1002/art.38048
189
J Ji , J Xu , S Zhao , F Liu , J Qi , Y Song , J Ren , T Wang , H Dou , Y Hou . Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs. Clin Sci (Lond) 2016; 130(16): 1453–1467 https://doi.org/10.1042/CS20160311
190
H Wu , Y Zhen , Z Ma , H Li , J Yu , ZG Xu , XY Wang , H Yi , YG Yang . Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci Transl Med 2016; 8(331): 331ra340 https://doi.org/10.1126/scitranslmed.aae0482
191
A Sobo-Vujanovic , L Vujanovic , AB DeLeo , F Concha-Benavente , RL Ferris , Y Lin , NL Vujanovic . Inhibition of soluble tumor necrosis factor prevents chemically induced carcinogenesis in mice. Cancer Immunol Res 2016; 4(5): 441–451 https://doi.org/10.1158/2326-6066.CIR-15-0104
192
H Lin , S Wei , EM Hurt , MD Green , L Zhao , L Vatan , W Szeliga , R Herbst , PW Harms , LA Fecher , P Vats , AM Chinnaiyan , CD Lao , TS Lawrence , M Wicha , J Hamanishi , M Mandai , I Kryczek , W Zou . Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 2018; 128(4): 1708 https://doi.org/10.1172/JCI120803
193
C Lu , PS Redd , JR Lee , N Savage , K Liu . The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells. OncoImmunology 2016; 5(12): e1247135 https://doi.org/10.1080/2162402X.2016.1247135
H Zhu , JD Klement , C Lu , PS Redd , D Yang , AD Smith , DB Poschel , J Zou , D Liu , PG Wang , D Ostrov , N Coant , YA Hannun , AH Colby , MW Grinstaff , K Liu . Asah2 represses the p53-Hmox1 axis to protect myeloid-derived suppressor cells from ferroptosis. J Immunol 2021; 206(6): 1395–1404 https://doi.org/10.4049/jimmunol.2000500
196
MK Srivastava , P Sinha , VK Clements , P Rodriguez , S Ostrand-Rosenberg . Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 2010; 70(1): 68–77 https://doi.org/10.1158/0008-5472.CAN-09-2587
197
DI Gabrilovich , S Nagaraj . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9(3): 162–174 https://doi.org/10.1038/nri2506
198
JI Youn , DI Gabrilovich . The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 2010; 40(11): 2969–2975 https://doi.org/10.1002/eji.201040895
199
DI Gabrilovich , V Bronte , SH Chen , MP Colombo , A Ochoa , S Ostrand-Rosenberg , H Schreiber . The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007; 67(1): 425 https://doi.org/10.1158/0008-5472.CAN-06-3037
200
S Ostrand-Rosenberg , DW Beury , KH Parker , LA Horn . Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment. Cancer Immunol Immunother 2020; 69(2): 215–221 https://doi.org/10.1007/s00262-019-02388-8
201
R Kim , A Hashimoto , N Markosyan , VA Tyurin , YY Tyurina , G Kar , SY Fu , M Sehgal , L Garcia-Gerique , A Kossenkov , BA Gebregziabher , JW Tobias , K Hicks , RA Halpin , N Cvetesic , H Deng , L Donthireddy , A Greenberg , B Nam , RH Vonderheide , Y Nefedova , VE Kagan , DI Gabrilovich . Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 2022; 612(7939): 338–346 https://doi.org/10.1038/s41586-022-05443-0
Q Cheng , LJ Mou , WJ Su , X Chen , T Zhang , YF Xie , J Xue , PY Lee , HX Wu , Y Du . Ferroptosis of CD163+ tissue-infiltrating macrophages and CD10+ PC+ epithelial cells in lupus nephritis. Front Immunol 2023; 14: 1171318 https://doi.org/10.3389/fimmu.2023.1171318
204
D Zhang , J Xu , J Ren , L Ding , G Shi , D Li , H Dou , Y Hou . Myeloid-derived suppressor cells induce podocyte injury through increasing reactive oxygen species in lupus nephritis. Front Immunol 2018; 9: 1443 https://doi.org/10.3389/fimmu.2018.01443
205
PP Yee , Y Wei , SY Kim , T Lu , SY Chih , C Lawson , M Tang , Z Liu , B Anderson , K Thamburaj , MM Young , DG Aregawi , MJ Glantz , BE Zacharia , CS Specht , HG Wang , W Li . Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat Commun 2020; 11(1): 5424 https://doi.org/10.1038/s41467-020-19193-y
206
D Wang , X Li , D Jiao , Y Cai , L Qian , Y Shen , Y Lu , Y Zhou , B Fu , R Sun , Z Tian , X Zheng , H Wei . LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia. J Hematol Oncol 2023; 16(1): 30 https://doi.org/10.1186/s13045-023-01429-1
207
H Zhang , J Liu , Y Zhou , M Qu , Y Wang , K Guo , R Shen , Z Sun , JP Cata , S Yang , W Chen , C Miao . Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci 2022; 18(8): 3337–3357 https://doi.org/10.7150/ijbs.69141
NA Carter , R Vasconcellos , EC Rosser , C Tulone , A Muñoz-Suano , M Kamanaka , MR Ehrenstein , RA Flavell , C Mauri . Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol 2011; 186(10): 5569–5579 https://doi.org/10.4049/jimmunol.1100284
210
F Flores-Borja , A Bosma , D Ng , V Reddy , MR Ehrenstein , DA Isenberg , C Mauri . CD19+ CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med 2013; 5(173): 173ra123 https://doi.org/10.1126/scitranslmed.3005407
211
NA Carter , EC Rosser , C Mauri . Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Res Ther 2012; 14(1): R32 https://doi.org/10.1186/ar3736
212
M Matsumoto , A Baba , T Yokota , H Nishikawa , Y Ohkawa , H Kayama , A Kallies , SL Nutt , S Sakaguchi , K Takeda , T Kurosaki , Y Baba . Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 2014; 41(6): 1040–1051 https://doi.org/10.1016/j.immuni.2014.10.016
213
CM Sun , E Deriaud , C Leclerc , R Lo-Man . Upon TLR9 signaling, CD5 B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. Immunity 2005; 22(4): 467–477 https://doi.org/10.1016/j.immuni.2005.02.008
214
J Tian , D Zekzer , L Hanssen , YX Lu , A Olcott , DL Kaufman . Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001; 167(2): 1081–1089 https://doi.org/10.4049/jimmunol.167.2.1081
215
VV Parekh , DVR Prasad , PP Banerjee , BN Joshi , A Kumar , GC Mishra . B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-β1. J Immunol 2003; 170(12): 5897–5911 https://doi.org/10.4049/jimmunol.170.12.5897
216
Z Pei , YF Qin , XH Fu , FF Yang , F Huo , X Liang , SJ Wang , HY Cui , P Lin , G Zhou , JN Yan , J Wu , ZN Chen , P Zhu . Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol 2022; 57: 102509 https://doi.org/10.1016/j.redox.2022.102509
