title: Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis.
abstract: 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 green fluorescent protein reporter mice revealed that regulatory T (Treg) cells were the predominant source of IL-10 in response to PGRN. In addition, PGRN-mediated expansion and activation of Tregcells, as well as IL-10 production, depends on JNK signaling, but not on known PGRN-activated ERK and PI3K pathways. Furthermore, microarray and chromatin immunoprecipitation sequencing screens led to the discovery of forkhead box protein O4 and signal transducer and activator of transcription 3 as the transcription factors required for PGRN induction of IL-10 in Tregcells. These findings define a previously unrecognized signaling pathway that underlies IL-10 production by PGRN in Tregcells and present new insights into the mechanisms by which PGRN resolves inflammation in inflammatory conditions and autoimmune diseases, particularly inflammatory arthritis.-Fu, W., Hu, W., Shi, L., Mundra, J. J. Xiao, G., Dustin, M. L., Liu, C. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis.
authors.affiliation: Department of Orthopaedic Surgery New York University Medical Center, New York, New York, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Fu
authors.affiliation: Memorial Hospital Research Laboratories, New York, New York, USA.
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Orthopaedic Surgery New York University Medical Center, New York, New York, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Orthopaedic Surgery New York University Medical Center, New York, New York, USA.
authors.forename: Jyoti Joshi
authors.initials: JJ
authors.lastname: Mundra
authors.affiliation: Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, China.|Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: GuoZhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.|Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Department of Orthopaedic Surgery New York University Medical Center, New York, New York, USA; chuanju.liu@nyumc.org.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Chuan-Ju
authors.initials: CJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008811:Mice, Inbred DBA; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000077153:Progranulins; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D000077153:Progranulins; D050796:STAT3 Transcription Factor; C525394:FoxO4 protein, mouse; C120204:Grn protein, mouse; C494087:Stat3 protein, mouse
keywords: JNK; TNFR2; Treg