Notch signaling and its emerging role in autoimmunity

doi:10.1007/s11515-012-1209-z

Front Biol

2013, Vol. 8

Issue (3) : 279-294 https://doi.org/10.1007/s11515-012-1209-z

REVIEW

Notch signaling and its emerging role in autoimmunity

Tanapat PALAGA¹, Lisa M. MINTER^2,3(

)

1. Department of Microbiology, Faculty of Science, Medical Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand; 2. Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA 01003, USA; 3. Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA

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Abstract

Studies of notch signaling in immune cells have uncovered critical roles for this pathway both during the differentiation and effector function phases of immune responses. Cells of the myeloid lineage, including macrophages and dendritic cells, function as key components of innate immune defense against infection and, by acting as antigen presenting cells, can instruct cells of the adaptive immune response, specifically CD4 and CD8 T cells. Tight regulation of this functional interaction is needed to ensure a well-balanced immune response and its dysregulation may indirectly or directly cause the tissue damage characteristic of autoimmune diseases. In this review, the focus will be placed on those recent findings which support a role for notch signaling in inflammatory responses mediated by macrophages and other myeloid lineage cells, as well as peripheral T cells, and their relevance to inflammatory and autoimmne diseases.

Keywords notch signaling inflammation autoimmunity

Corresponding Author(s): MINTER Lisa M.,Email:lminter@vasci.umass.edu

Issue Date: 01 June 2013

Cite this article:

Tanapat PALAGA,Lisa M. MINTER. Notch signaling and its emerging role in autoimmunity[J]. Front Biol, 2013, 8(3): 279-294.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1209-z
https://academic.hep.com.cn/fib/EN/Y2013/V8/I3/279

Fig.1 Activation and inhibition of notch signaling. Following ligand binding notch receptors are sequentially cleaved to release their intracellular, transcriptionally active components. This includes cleavage at the S2 site by an ADAM protease followed by cleavage at the S3 site by a gamma-secretase containing complex. Cleavage by gamma-secretase liberates the signaling-competent intracellular domain of notch (NICD), which translocates to the nucleus and interacts with its canonical nuclear binding partners, MAML and RBPjκ/CSL to transcribe notch target genes. Notch signaling can be inhibited genetically or pharmacologically, as indicated in red above.

Cell type	Notch receptors	Notch ligands	References
Myeloid lineage
(1) Monocyte/macrophage
Mice	Notch1, 2, 3, 4(RT-PCR, Western blot, Flow cytometry)	Jag1, Dll1, Dll4(RT-PCR)	J?nsson et al., 2001; Monsalve et al., 2006; Palaga et al., 2008; Zhang et al., 2010
Human	Notch1, 2, 3, 4 (RT-PCR, Western blot)	Jag1, Dll1, Dll4(RT-PCR, Western blot)	Fung et al., 2007; Foldi et al., 2010
(2) Granulocytes
Mice	Notch1, 2(RT-PCR)	Jag1, Jag2(RT-PCR)	Singh et al., 2000; J?nsson et al., 2001; Yamaguchi et al., 2002
Human eosinophils	Notch1, 2(RT-PCR, Flow cytometry)	Jag1, Jag2(Western blot, Flow cytometry)	Radke et al., 2009
(3) Mast cells
Mice	Notch1, 2(Flow cytometry)	Jag1(RT-PCR)	Singh et al., 2000; Nakano et al., 2011; Sakata-Yanagimoto et al., 2011
(4) Dendritic cells
Mice	Notch1, 2(RT-PCR, Western blot)	Jag1, Jag2, Dll1, Dll3, Dll4(RT-PCR, Western blot)	Cheng et al., 2010; Hoyne et al., 2000; Weijzen et al., 2002; Yamaguchi et al., 2002
Human	Notch1, 2(Flow cytometry, immunofluorescence)	Jag1, Jag2, Dll1, Dll4(Flow cytometry, immunofluorescence)	Pérez-Cabezas et al., 2011
Lymphoid lineage
(5) CD4 T cells
Mice	Notch1i(4), 2i(24), 3i(24), 4(Flow cytometry; RT-PCR; Western blot)	Jag1, Jag2i, w(48)(qRT-PCR, Flow cytometry)	Adler et al., 2003;Palaga et al., 2003; Amsen et al., 2004; Benson et al., 2005; Minter et al., 2005; Jurynczyk et al., 2008; Moriyama et al., 2008; Fiorini et al., 2009; Koyanagi et al., 2012
Human	Notch1i(24)(Flow cytometry, Western blot)		Keerthivasan et al., 2011; Minter, unpublished results
(6) CD8 T cells
Mice	Notch1i(4), 2i(24), 3i(24)(Flow cytometry)	Jag2i, w(48)(Flow cytometry)	Palaga et al., 2003; Fiorini et al., 2009; Koyanagi et al., 2012
Human	Notch1i(12)(Flow cytometry)		Minter, unpublished results
(7) Th1 cells
**Mice	Notch1⁺⁺⁺, 2⁺⁺⁺ , 3i(24)(Flow cytometry)	None detected(Flow cytometry)	Maekawa et al., 2003; Minter et al., 2005; Koyanagi et al., 2012
Human	Notch1⁺⁺⁺(Flow cytometry)		Minter, unpublished results
(8) Th2 cells
**Mice	Notch1⁺⁺ , 2⁺, 3w, i (24)(Flow cytometry)	None detected(Flow cytometry)	Minter et al., 2005; Koyanagi et al., 2012
(9) Th17 cells
**Mice	Notch1⁺, 2w, 3i(24)(Flow cytometry, Western blot)	None detected(Flow cytometry)	Keerthivasan et al., 2011; Koyanagi et al., 2012
Human	Notch1(Western blot)		Keerthivasan et al., 2011
(10) T regulatory cells
Mice	Notch1i(24), 2w, i(24), 3vw, i(24)(Flow cytometry)	Jag1, Jag2vw, Dll1, Dll4(Flow cytometry)	Kared et al., 2006; Ostroukhova et al., 2006; Koyanagi et al., 2012
(11) CD19⁺ B cells
Mice	Notch1, 2(RT-PCR, Flow cytometry)		Moriyama et al., 2008; Bertrand et al., 2000
Human	Notch1(RT-PCR)		Bertrand et al., 2000

Tab.1 Summarized expression of notch receptors and ligands in immune cells

Fig.2 Notch signaling regulates effector functions of myeloid lineage cells. PRR-recognition of their specific ligands initiates the activation of notch signaling. Notch receptors are engaged by different ligands which are induced upon activation of the myeloid lineage cells. The activation of notch signaling functions cooperatively with other signaling pathways to produce a wide array of outcomes. It promotes pro-inflammatory responses in macrophages and regulates migration and effector functions of other myeloid lineage cells.

Fig.3 Notch signaling in autoimmune diseases. Notch signaling has been implicated in various autoimmune conditions including systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis/multiple sclerosis, immune thrombocytopenia purpura, and aplastic anemia. Increased or decreased expression of individual notch receptors and/or ligands may be disease specific and, as such, may provide useful biomarkers of disease or targets for therapeutic intervention. See text for discussion of individual autoimmune conditions and notch receptor/ligand expression.

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