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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2023, Vol. 17 Issue (4) : 781-795    https://doi.org/10.1007/s11684-023-0986-x
RESEARCH ARTICLE
Hyperosmolarity promotes macrophage pyroptosis by driving the glycolytic reprogramming of corneal epithelial cells in dry eye disease
Yu Han, Yu Zhang, Kelan Yuan, Yaying Wu, Xiuming Jin, Xiaodan Huang()
Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou 310009, China
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Abstract

Tear film hyperosmolarity plays a core role in the development of dry eye disease (DED) by mediating the disruption of ocular surface homeostasis and triggering inflammation in ocular surface epithelium. In this study, the mechanisms involving the hyperosmolar microenvironment, glycolysis mediating metabolic reprogramming, and pyroptosis were explored clinically, in vitro, and in vivo. Data from DED clinical samples indicated that the expression of glycolysis and pyroptosis-related genes, including PKM2 and GSDMD, was significantly upregulated and that the secretion of IL-1β significantly increased. In vitro, the indirect coculture of macrophages derived from THP-1 and human corneal epithelial cells (HCECs) was used to discuss the interaction among cells. The hyperosmolar environment was found to greatly induce HCECs’ metabolic reprogramming, which may be the primary cause of the subsequent inflammation in macrophages upon the activation of the related gene and protein expression. 2-Deoxy-d-glucose (2-DG) could inhibit the glycolysis of HCECs and subsequently suppress the pyroptosis of macrophages. In vivo, 2-DG showed potential efficacy in relieving DED activity and could significantly reduce the overexpression of genes and proteins related to glycolysis and pyroptosis. In summary, our findings suggested that hyperosmolar-induced glycolytic reprogramming played an active role in promoting DED inflammation by mediating pyroptosis.
Keywords dry eye disease      glycolytic reprogramming      pyroptosis      inflammation      2-DG     
Corresponding Author(s): Xiaodan Huang   
Just Accepted Date: 11 April 2023   Online First Date: 22 May 2023    Issue Date: 12 October 2023
 Cite this article:   
Yu Han,Yu Zhang,Kelan Yuan, et al. Hyperosmolarity promotes macrophage pyroptosis by driving the glycolytic reprogramming of corneal epithelial cells in dry eye disease[J]. Front. Med., 2023, 17(4): 781-795.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0986-x
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I4/781
Gene Forward primer sequence Reverse primer sequence
Human-NLRP3 5′-GATCTTCGCTGCGATCAACAG-3′ 5′-CGTGCATTATCTGAACCCCAC-3′
Human-caspase-1 5′-TTTCCGCAAGGTTCGATTTTCA-3′ 5′-GGCATCTGCGCTCTACCATC-3′
Human-GSDMD 5′-GTGTGTCAACCTGTCTATCAAGG-3′ 5′-CATGGCATCGTAGAAGTGGAAG-3′
Human-IL-1β 5′-ATGATGGCTTATTACAGTGGCAA-3′ 5′-GTCGGAGATTCGTAGCTGGA-3′
Human-HK1 5′-GCTCTCCGATGAAACTCTCATAG-3′ 5′-GGACCTTACGAATGTTGGCAA-3′
Human-TPI1 5′-CTCATCGGCACTCTGAACG-3′ 5′-GCGAAGTCGATATAGGCAGTAGG-3′
Human-GAPDH 5′-GGAGCGAGATCCCTCCAAAAT-3′ 5′- GGCTGTTGTCATACTTCTCATGG-3′
Human-PGAM 5′-TCTGGAGGCGCTCCTATGAT-3′ 5′-TCTGTGAGGTCTGCATACCTG-3′
Human-ENO1 5′-GCCGTGAACGAGAAGTCCTG-3′ 5′-ACGCCTGAAGAGACTCGGT-3′
Human-PKM2 5′-ATGTCGAAGCCCCATAGTGAA-3′ 5′-TGGGTGGTGAATCAATGTCCA-3′
Mouse-Nlrp3 5′-TGTGAGAAGCAGGTTCTACTCT-3′ 5′-TGTAGCGACTGTTGAGGTCCA-3′
Mouse-caspase-1 5′-AATACAACCACTCGTACACGTC-3′ 5′-AGCTCCAACCCTCGGAGAAA-3′
Mouse-Gsdmd 5′-TTCCAGTGCCTCCATGAATGT-3′ 5′-GCTGTGGACCTCAGTGATCT-3′
Mouse-Il-1β 5′-GAAATGCCACCTTTTGACAGTG-3′ 5′-TGGATGCTCTCATCAGGACAG-3′
Mouse-Pkm2 5′-CGCCTGGACATTGACTCTG-3′ 5′-GAAATTCAGCCGAGCCACATT-3′
Tab.1  RT-qPCR primer
Fig.1  Study of glycolysis and pyroptosis levels in DED patients. (A) Quantification of IL-1β titer in the tears of DED patients and healthy controls by ELISA. RT-qPCR was used to detect the gene expressions of NLRP3 (B), caspase-1 (C), GSDMD (D), IL-1β (E), HK1 (F), TPI1 (G), GAPDH (H), PGAM (I), ENO1 (J), and PKM2 (K) in ocular surface cells collected by CIC from DED patients and healthy controls. Data are represented as mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001 between the two groups.
Fig.2  Glycolysis and pyroptosis level changes in the cornea of the DED mouse model. (A) Tear secretion was examined by the Schirmer test in MRL/MPJ control mice and MRL/lpr DED mice. (B) Lactate concentrations were detected in the cornea by lactate assay. Data were analyzed by t-test and are represented as mean ± SD; *P < 0.05 and **P < 0.01. (C) Quantifications of Nlrp3, caspase-1, Gsdmd, and Il-1β gene expressions in the cornea by RT-qPCR. Data were analyzed by one-way ANOVA and are represented as mean ± SD (n = 3); * P < 0.05, ** P < 0.01, and *** P < 0.001. (D) Protein expression levels of PKM2, cleaved-caspase-1, cleaved-gasdermin D, and cleaved-IL-1β detected in the cornea by Western blot analysis. The representative immunoblots and protein quantification were analyzed by t-test; * P < 0.05 and *** P < 0.001. (E) TUNEL assay-labeled death cells in mouse cornea; death cells are labeled in green, and cell nucleus are in blue. Scale bar = 50?μm (20×). Quantitation of the ratio of TUNEL positive cells to total cells was performed through TUNEL staining. Data are represented as mean ± SD; **P < 0.01, compared with the control group (t-test). Representative images (F) of staining macrophages (F4/80, red) infiltrating the mouse corneas. Scale bar = 100?μm (40×). Quantitation of the ratio of F4/80 positive cells to total cells was conducted by IHC staining. Data are represented as mean ± SD; *P < 0.05, compared with the control group (t-test).
Fig.3  Regulation effect of glycolysis and pyroptosis in the dry eye microenvironment model in vitro. (A) Gene expressions of HK1, GPI, PFKM, ALDOA, TPI1, ENO1, PGK1, PGAM, and PKM2 in HCECs after treatment with 2-DG (10 mM) and HM (450 mOsM). Control cells were cultured in an isotonic medium (IM; 312 mOsM). Data are represented as mean ± SD (n = 3); *P < 0.05, **P < 0.01, and ***P < 0.001 (one-way ANOVA). (B) HK1, PFKM, PKM2, LDH, and PDH protein expressions in HCECs after treatment with 2-DG and HM. Data are represented as mean ± SD; *P < 0.05 (one-way ANOVA). (C) With or without 2-DG pretreatment, the level of lactic acid secretion was detected in HCEC treatment with HM by ELISA. Data are represented as mean ± SD; **P < 0.001 (one-way ANOVA). (D) Schematic of the indirect coculture model of HCECs and THP-1 in a Transwell chamber. (E) Pyroptosis-related protein (NLRP3, cleaved-caspase-1, cleaved-gasdermin D, and cleaved-IL-1β) expression levels in THP-1 examined by Western blot after coculture with HCEC supernatant. The representative immunoblots and protein quantification were analyzed by one-way ANOVA; *P < 0.05 and ***P < 0.001, compared with HM; #P < 0.05, compared with IM. (F) ROS level of THP-1 examined by flow cytometry after coculture with HCEC supernatant. Data are represented as mean ± SD; ***P < 0.001, compared with IM (312 mOsM), t-test.
Fig.4  Level of glycolysis and pyroptosis in the dry eye microenvironment model after siRNA-mediated gene silencing. (A) The expression levels of the targeted genes were knocked down by specific siRNA in HCECs and HCEC-specific gene-knockdown cells. (B) After siRNA-mediated gene silencing, the level of lactic acid secretion was detected in HCEC and HCEC-specific gene-knockdown cell treatments with HM by ELISA. Data were analyzed by one-way ANOVA; *P < 0.05, compared with HM; #P < 0.05, compared with IM. (C) Levels of glycolysis (HK1, PFKM, PKM2, LDH, and PDH)-related protein expression in HCECs and pyroptosis (NLRP3, cleaved-caspase-1, cleaved-GSDMD, and cleaved-IL-1β)-related protein expression in macrophages derived from THP-1 after siHK1 treatment and coculture. (D) Level of glycolysis (HK1, PFKM, PKM2, LDH, and PDH)-related protein expression in HCECs and pyroptosis (NLRP3, cleaved-caspase-1, cleaved-GSDMD, and cleaved-IL-1β)-related protein expression in macrophages derived from THP-1 after siPKM2 treatment and coculture. The representative immunoblots and protein quantification were analyzed by one-way ANOVA; *P < 0.05, **P < 0.01, and ***P < 0.001, compared with HM; ###P < 0.05, ###P < 0.01, and ###P < 0.001, compared with IM.
Fig.5  Level of pyroptosis in THP-1 after inhibiting glycolysis in HCECs in the dry eye microenvironment model. (A) Representative images of THP-1 cells after coculturing with the supernatant of HCECs pretreated with IM, HM, 2-DG, siPKM2, or siHK1 under an optical microscope. The red arrow indicated air bubbles. (B, C) TUNEL and PI staining indicated the cell death of THP-1 in the dry eye microenvironment model. Cell death is labeled in green (TUNEL) and red (PI), and cell nucleus is in blue (DAPI).
Fig.6  2-DG inhibited glycolysis and pyroptosis in the cornea of dry eye mice. (A) Treatment of 2-DG (250 mg/kg/day) on tear secretion (Schirmer test) in control and DED mice. (B) Levels of cell death and macrophage infiltration in the cornea of DED mice treated with 2-DG. TUNEL-labeled death cells (green), F4/80-labeled macrophages (red), and DAPI-labeled cell nucleus (blue). Scale bar = 100?μm (40×). Data are represented as mean ± SD; **P < 0.01, compared with the control group, t-test. (C) 2-DG downregulated the level of pyroptosis through glycolysis inhibition in the cornea of DED mice. Cornea tissue lysates were analyzed by Western blot for PKM2, NLRP3, cleaved-Caspase-1, cleaved-gasdermin D, cleaved-IL-1β, and β-actin (as loading control). Representative Western blots and the protein quantification are shown: ###P < 0.001, compared with the control group; ***P < 0.001, compared with DED mice (one-way ANOVA).
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