Cutting Edge: c-Kit Signaling Differentially Regulates Type 2 Innate Lymphoid Cell Accumulation and Susceptibility to Central Nervous System Demyelination in Male and Female SJL Mice

Abstract

Multiple sclerosis (MS) preferentially affects women and this sex dimorphism is recapitulated in the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that signaling through c-kit exerts distinct effects on EAE susceptibility in male and female SJL mice. Previous studies in females show that Kit mutant (W/Wv) mice are less susceptible to EAE than wildtype mice. However, male W/Wv mice exhibit exacerbated disease, a phenotype independent of mast cells and corresponding to a shift from a Th2 to a Th17 dominated T cell response. We demonstrate a previously undescribed deficit in c-kit+ type 2 innate lymphoid cells (ILC2s) in W/Wv mice. ILC2s are also significantly reduced in EAE-susceptible WT females indicating that both c-kit signals and undefined male-specific factors are required for ILC2 function. We propose that deficiencies in Th2-promoting ILC2s removes an attenuating influence on the encephalitogenic T cell response and therefore increases disease susceptibility.

Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

“…The presence or function of potential CNS ILC2s has been studied only at the most peripheral level, with only 2 studies attempting to study them Russi et al, 2015).…”

“…The second study by Russi et al looked when they attempted to rescue the defect with mast cell reconstitution it had no effect (Russi et al, 2015). Puzzled with this result, the authors looked to other cell types, discovering that SJL-W/W v animals were also deficient in ILC2s (Russi et al, 2015).…”

“…Puzzled with this result, the authors looked to other cell types, discovering that SJL-W/W v animals were also deficient in ILC2s (Russi et al, 2015). They were able to detect ILC2s in the CNS (pooled brain and spinal cord) by flow in naïve animals, and the numbers increased 10 days post EAE induction.…”

“…They were able to detect ILC2s in the CNS (pooled brain and spinal cord) by flow in naïve animals, and the numbers increased 10 days post EAE induction. These ILC2s produced type 2 cytokines differentially in male versus female mice, and the authors proposed this as potentially contributing to the clear female bias in MS incidence (Russi et al, 2015).…”

“…Though ILC2s had previously been implicated in CNS diseases (Russi et al, 2015;Besnard et al, 2015), their presence in the healthy meninges has not been established. We therefore To explore the physical localization of ILC2s within the meninges we crossed the IL-13 cre and tdTomato stoplox (IL-13 tdT ) mice, generating a model that labels any cell that has even made IL-13.…”