Foxo4 and Stat3 dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis

Progranulin (PGRN) restrains inflammation and is therapeutic against inflammatory arthritis; however, the underlying immunological mechanism remains unknown. In this study we demonstrated that anti-inflammatory cytokine IL-10 was a critical mediator for PGRN-mediated anti-inflammation in collagen-induced arthritis by using PGRN and IL-10 genetically modified mouse models. IL-10 GFP reporter mice revealed that regulatory T cells (Treg) were the predominant source of IL-10 in response to PGRN. In addition, PGRN-mediated expansion and activation of Tregs as well as IL-10 production depends on JNK signaling, but not on known PGRN-activated ERK and PI3k pathways. Furthermore, Microarray and ChIP-Seq screens led to the discovery of Foxo4 and Stat3 as the transcription factors required for PGRN induction of IL-10 in Tregs. These findings defines a previously unrecognized signaling pathway underlying IL-10 production by PGRN in Tregs, and present new insights into the mechanisms by which PGRN resolves inflammation in inflammatory conditions and autoimmune diseases, in particular, inflammatory arthritis