PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner

This study was aimed to determine the role and regulation of progranulin (PGRN) in the pathogenesis of inflammatory bowel diseases (IBD). Dextran sulfate sodium (DSS)-, picrylsulfonic acid (TNBS)-induced, bone marrow chimera and CD4+CD45Rb(hi) T cell transfer colitis model were established and analy...

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Bibliographic Details
Published in:Scientific reports 2014-11, Vol.4 (1), p.7023-7023, Article 7023
Main Authors: Wei, Fanhua, Zhang, Yuying, Jian, Jinlong, Mundra, Jyoti Joshi, Tian, Qingyun, Lin, Jiqiang, Lafaille, Juan Jose, Tang, Wei, Zhao, Weiming, Yu, Xiuping, Liu, Chuan-Ju
Format: Article
Language:English
Subjects:
Animal models
Animals
Anti-Inflammatory Agents, Non-Steroidal - metabolism
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Bone marrow
Bone Marrow - immunology
Bone Marrow - pathology
CD4 antigen
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD4-Positive T-Lymphocytes - pathology
Chimeras
Colitis
Colon
Dextran
Dextran Sulfate
Disease Models, Animal
Disease Progression
Gene Expression Regulation
Humans
Inflammatory bowel disease
Inflammatory bowel diseases
Inflammatory Bowel Diseases - chemically induced
Inflammatory Bowel Diseases - drug therapy
Inflammatory Bowel Diseases - genetics
Inflammatory Bowel Diseases - pathology
Intercellular Signaling Peptides and Proteins - deficiency
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - pharmacology
Interleukin 10
Interleukin-10 - deficiency
Interleukin-10 - genetics
Intestine
Lymphocytes T
Mice
Mice, Knockout
Receptors, Tumor Necrosis Factor, Type II - deficiency
Receptors, Tumor Necrosis Factor, Type II - genetics
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Recombinant Proteins - pharmacology
Rodents
Signal Transduction
Sodium
Sulfates
Transplantation Chimera
Trinitrobenzenesulfonic Acid
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Summary:This study was aimed to determine the role and regulation of progranulin (PGRN) in the pathogenesis of inflammatory bowel diseases (IBD). Dextran sulfate sodium (DSS)-, picrylsulfonic acid (TNBS)-induced, bone marrow chimera and CD4+CD45Rb(hi) T cell transfer colitis model were established and analyzed in wild-type and several genetically-modified mice, including PGRN, IL-10 and TNFR2 deficient mice. Elevated levels of PGRN were found in colitis samples from human IBD patients and mouse colitis models in comparison to the corresponding controls. PGRN-deficient mice became highly susceptible to DSS- and TNBS-induced colitis, whereas recombinant PGRN ameliorated the pathology and reduced the histological score in both DSS and TNBS colitis models. In addition, hematopoietic-derived PGRN was critical for protection against DSS-induced colitis, and lack of PGRN signaling in CD4+ T cells also exacerbated experimental colitis. PGRN-mediated protective effect in colitis was compromised in the absence of IL-10 signaling. In addition, PGRN's effect was also largely lost in the TNFR2-deficient colitis model. Collectively, these findings not only provide the new insight into PGRN's anti-inflammatory action in vivo, but may also present PGRN and its derivatives as novel biological agent for treating IBD.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep07023