Interleukin-37 Suppresses CNS Autoimmunity by Stimulating an Amphiregulin-IL-10 Axis

Interleukin (IL)-37, a novel member of the IL-1 family of cytokines, has anti-inflammatory properties. It was shown that IL-37 suppresses innate immunity and allergic reactions by modulating dendritic cells (DCs) and mast cells and interfering with the mTOR pathway. Although multiple sclerosis (MS) patients have increased serum levels of IL-37; it is currently unknown whether IL-37 has a protective role in autoimmune neuroinflammation. Here we show that IL-37 suppresses experimental autoimmune encephalomyelitis (EAE), the prototypical animal model of MS, by ultimately inducing IL-10+ B cells. B cell-derived IL-10 was critical for EAE suppression when mice were treated with IL-37; however, IL-37 did not directly induce IL-10 in B cells. Instead, IL-37 triggered the mTORC2 pathway in DCs, leading to production of the tissue repair-associated cytokine amphiregulin (Areg), which stimulated CD4+ T cells to produce IL-21 and DCs to produce IL-27. Blockade of Areg, IL-21 and IL-27 revoked the protective effects of IL-37 by precluding an increase in the frequency of IL-10+ B cells. Our results describe an IL-37-Areg-IL-10 transcellular circuit that suppresses CNS autoimmune inflammation that can be further explored in future therapies for MS and other neuroinflammatory conditions.