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

• Published in: The FASEB journal 2017-04, Vol.31 (4), p.1354-1367
• Main Authors: Fu, Wenyu, Hu, Wenhuo, Shi, Lei, Mundra, Jyoti Joshi, Xiao, GuoZhi, Dustin, Michael L., Liu, Chuan‐ju
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animal models; Animals; Arthritis; Arthritis, Experimental - metabolism; Autoimmune diseases; Cells, Cultured; Chromatin; Collagen; DNA microarrays; Fluorescence; Forkhead protein; Forkhead Transcription Factors - metabolism; FOXO4 protein; Genetic modification; Green fluorescent protein; Immunology; Immunoprecipitation; Immunoregulation; Inflammation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; JNK; JNK protein; Lymphocytes; Lymphocytes T; MAP Kinase Signaling System; Mice; Mice, Inbred DBA; Phosphatidylinositol 3-Kinases - metabolism; Screens; Signal transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; TNFR2; Transcription factors; Treg
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201601134R

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 Treg cells, 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 Treg cells. These findings define a previously unrecognized signaling pathway that underlies IL‐10 production by PGRN in Treg cells 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. FASEB J. 31, 1354–1367 (2017) www.fasebj.org