c-kit plays a critical role in induction of intravenous tolerance in experimental autoimmune encephalomyelitis

Abstract

c-Kit (CD117) is a tyrosine kinase receptor found in various types of immune cells. It has been shown that c-Kit plays a role in the pathogenesis of multiple sclerosis, an inflammatory demyelinating disorder of the CNS. Recent data have suggested an immunoregulatory effect of c-Kit. We therefore examined the role of c-Kit in autoantigen-induced i.v. tolerance in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our results show that induction of intravenous tolerance against EAE in B6 mice is characterized by increased numbers of CD117+ cells and altered mast-cell associated molecules in the periphery and in the CNS. W−sh (c-Kit deficient) mice were resistant to i.v autoantigen-induced tolerance, with increased proinflammatory cytokine production in the periphery. I.v. autoantigen in WT mice suppressed production of proinflammatory cytokines IFN-γ and IL-6 and up-regulated expression of FoxP3, a transcription factor of Tregs; however, in W−sh mice IFN-γ and IL-6 were increased with a failure of FoxP3 induction upon i.v. autoantigen injection, and is thus a mechanism for resistance to i.v. tolerance induction in these mice. We conclude that c-kit signaling has a regulatory role in i.v. tolerance and could be a target for potential immunotherapy in autoimmune disorders.

Selective depletion of CD11c+CD11b+ dendritic cells partially abrogates tolerogenic effects of intravenous MOG in murine EAE

“…Clonal deletion and anergy of antigen‐specific Th1/Th17 cells and induction of Treg cells are the main mechanisms involved in the induction of i.v. tolerance .…”

Expression of platelet‐derived growth factor receptor‐α/ß, vascular endothelial growth factor receptor‐2, c‐Abl, and c‐Kit in canine granulomatous meningoencephalitis and necrotizing encephalitis

“…c-Kit is a stem cell factor receptor and acts as a key controller receptor for mast cell development and functioning (Maeda, Nishiyama, Ogawa, & Okumura, 2010;Maeda et al, 2001). The high expression of c-kit in mast cells enhances their cell development, degranulation and release of chemokines and cytokines (Safavi et al, 2015). Mast cells are a dense cell population in the meninges and near the vessels involved in MS and EAE (Sayed, Christy, Quirion, & Brown, 2008).…”

Innate Lymphoid Cells (Non‐NK ILCs)

“…Similarly, in the mouse model of multiple sclerosis, EAE, ILC3 presence in the brain was reported. More importantly, ILC3 number or activity is also described in MS patients blood and CSF [119][120][121][122]. In both of these autoimmune conditions, how actually ILC3s impact the disease progression is yet to be defined.…”