Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is widely used to dissect molecular mechanisms of MS and to develop new therapeutic strategies. Studies of EAE have helped define the sequence of events involved in the development of autoimmune CNS-directed inflammatory diseases, including the initiation stage (activation and expansion of neuroantigen-reactive CD4 T lymphocytes outside of CNS) and effector stage (recruitment and reactivation of neuroantigen-reactive CD4 T lymphocytes and subsequent inflammatory response within CNS). Recent studies have shown that a distinct CD4 T cell lineage -Th17 cells driven by TGF /IL-6/IL-23 play a critical role in the development of EAE. IL-17 produced by Th17 functions as an inflammatory cytokine and plays an important role in the pathogenesis of EAE by upregulating the expression of cytokines and chemokines. EAE is markedly suppressed in mice lacking IL-17 or IL-17 receptor. Studies using IL-17-specific inhibition indicate that IL-17-mediated signaling plays a critical role in the effector stage of EAE. We and others have identified Act1 as an essential IL-17 signaling molecule recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation through SEFIR-SEFIR domain interaction. We recently reported that Act1 is a novel bona fide U-box E3 ubiquitin ligase, whose activity is essential for IL-17-mediated signaling and inflammatory gene expression. While IL-17 plays an essential role in the development of EAE, it remains unclear how IL-17-mediated signaling in different cellular compartments participates in the CNS in EAE. We now show that Th17 cells are robustly generated in Act1-deficient mice and normally infiltrate the Act1-deficient CNS but fail to recruit hematogenously derived lymphocytes, neutrophils, and macrophages into the CNS. Importantly, Act1 deficiency in endothelial cells or in macrophages/microglia did not substantially impact the development of EAE. However, targeted Act1 deficiency in neuroectoderm derived CNS resident cells (including astrocytes, oligodendrocytes and neurons) resulted in significantly reduced EAE severity whether EAE was induced by active immunization or adoptive transfer of myelin-specific Th17 cells. Based on these findings, we hypothesize that IL-17-induced Act1-mediated signaling in different CNS resident cells coordinately mediate leukocyte recruitment, demyelination and neurodegeneration during autoimmune induced inflammation of the CNS. To test this hypothesis, we propose the following Specific Aims:
Aim 1 : Investigate the cellular mechanism of IL-17 signaling in the Th17-mediated pathogenesis of EAE.
Aim 2 : Elucidate the molecular mechanism by which Act1 mediates IL-17 signaling and develop decoy (inhibitory) peptides as a new therapeutic strategy for CNS inflammation, demyelination and neurodegeneration.
The proposed study is aimed to comprehensively delineate how IL-17-mediated signaling in various cellular compartments contributes to Th17-induced EAE. Defining the precise role of Act1 in EAE pathogenesis and understanding the molecular mechanisms by which Act1 mediates IL-17 signaling in CNS resident cells will provide us new opportunities for developing therapeutic strategies to alleviate MS. Considering the critical role of IL-17 in various inflammatory and autoimmune diseases, it is highly significant to investigate the mechanistic role of IL-17 signaling in the disease process, which is very critical for the development of new strategies to attenuate Th17-mediated pathogenesis.
|Martin, Bradley N; Wang, Chenhui; Zhang, Cun-jin et al. (2016) T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583-92|
|Zhou, Wenchao; Ke, Susan Q; Huang, Zhi et al. (2015) Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 17:170-82|
|Wu, Ling; Chen, Xing; Zhao, Junjie et al. (2015) A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. J Exp Med 212:1571-87|
|Zepp, Jarod A; Wu, Ling; Qian, Wen et al. (2015) TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation. J Immunol 194:2826-37|
|Wu, Ling; Zepp, Jarod A; Qian, Wen et al. (2015) A novel IL-25 signaling pathway through STAT5. J Immunol 194:4528-34|
|Taylor, Patricia R; Roy, Sanhita; Leal Jr, Sixto M et al. (2014) Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORÃ½Ã½t and dectin-2. Nat Immunol 15:143-51|
|Wu, Ling; Wang, Chenhui; Boisson, Bertrand et al. (2014) The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling. J Immunol 193:1590-9|
|Zhang, Bing; Liu, Caini; Qian, Wen et al. (2014) Structure of the unique SEFIR domain from human interleukin 17 receptor A reveals a composite ligand-binding site containing a conserved Î±-helix for Act1 binding and IL-17 signaling. Acta Crystallogr D Biol Crystallogr 70:1476-83|
|Martin, Bradley N; Wang, Chenhui; Willette-Brown, Jami et al. (2014) IKKÎ± negatively regulates ASC-dependent inflammasome activation. Nat Commun 5:4977|
|Giltiay, Natalia V; Lu, Yi; Cullen, Jaime L et al. (2013) Spontaneous loss of tolerance of autoreactive B cells in Act1-deficient rheumatoid factor transgenic mice. J Immunol 191:2155-63|
Showing the most recent 10 out of 23 publications