1. Foxo4 and Stat3 dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis
- Author
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Wenyu Fu, Jyoti Joshi Mundra, Guozhi Xiao, Lei Shi, Michael L. Dustin, Chuan-ju Liu, and Wenhuo Hu
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,MAP Kinase Signaling System ,medicine.medical_treatment ,Inflammatory arthritis ,Arthritis ,Inflammation ,Cell Cycle Proteins ,Biochemistry ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Progranulins ,Genetics ,medicine ,Animals ,STAT3 ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Granulins ,biology ,Research ,Forkhead Transcription Factors ,medicine.disease ,Arthritis, Experimental ,Cell biology ,Interleukin-10 ,Interleukin 10 ,030104 developmental biology ,Cytokine ,Mice, Inbred DBA ,FOXO4 ,biology.protein ,Intercellular Signaling Peptides and Proteins ,medicine.symptom ,030215 immunology ,Biotechnology - 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 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.
- Published
- 2017