Pathogenic role of ILC2 in rheumatoid arthritis

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ABSTRACT The pathogenesis of rheumatoid arthritis (RA) involves a complex interplay between adaptive (e.g. T & B cells) and innate (e.g. macrophages) immune cells and mesenchymal-derived stromal cells (e.g. local fibroblast-like synoviocytes [FLS]). Immune cell-mediated activation of FLS plays a key role in joint inflammation and destruction during RA. This project will explore a novel mechanism of activation of FLS by the ILC2 subset of innate lymphoid cells (ILCs). ILCs are recently discovered immune cells that are enriched in peripheral tissues and act as the first local barrier against infections and tumors. Four major subsets of ILCs have been identified, ILC1, ILC2, ILC3 and cNK cells that display immune functions similar to those of Th1, Th2, and Th17 subsets of CD4 T cells and CD8 killer T cells respectively. Of these, ILC2 are homologous to Th2 cells and secrete “type 2 cytokines” such as interleukin-4 (IL-4), IL-5 and IL-13, which drive a “type 2” immune response. The type 2 immune response is considered to be anti-inflammatory in RA, however it remains unclear whether ILC2 exclusively play a disease protective role in RA. The objective of this grant is to collect pilot evidence that ILC2 play a pathogenic role in RA by secreting an epidermal growth factor (EGF)-similar molecule called amphiregulin (AREG). ILC2 are known to secrete AREG which normally helps to maintain tissue integrity in response to infections, but is also implicated in the pathogenesis of organ fibrosis in the context of chronic inflammation. We have found high levels of AREG -mainly produced by ILC2- in the joints of arthritic mice and have preliminary evidence that AREG promotes arthritis severity and the aggressive behavior of fibroblast-like synoviocytes (FLS) in vitro. We thus hypothesize that joint-localized ILC2 promote disease activity in RA through interaction with FLS via production of AREG. This grant application proposes experiments aimed to obtain rigorous evidence that ILC2 enhance development of arthritis in mice through production of AREG (Aim 1), and that AREG promotes aggressive and joint-destructive behavior in FLS in vitro and in vivo (Aim 2). The project fits well with the R21 format because the objective is to collect pilot evidence in support of a concept that is currently considered high risk and potentially counterintuitive, however, if validated, it might pave the way to novel therapeutic approaches to RA via interference with the ILC2-AREG-FLS axis. .