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 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.
1] Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003 [2] Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012.
Fanhua
F
Wei
Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003.
Yuying
Y
Zhang
Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003.
Jinlong
J
Jian
Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003.
Jyoti Joshi
JJ
Mundra
Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003.
Qingyun
Q
Tian
Department of Pathology, New York University Medical Center, New York, NY, 10016.
Jiqiang
J
Lin
Department of Pathology, New York University Medical Center, New York, NY, 10016.
Juan Jose
JJ
Lafaille
Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012.
Wei
W
Tang
Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012.
Weiming
W
Zhao
Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012.
Xiuping
X
Yu
1] Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003 [2] Department of Cell Biology, New York University School of Medicine, New York, NY 10016.
Chuan-Ju
CJ
Liu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D000077155:Granulins; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000077153:Progranulins; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D018183:Transplantation Chimera; D014302:Trinitrobenzenesulfonic Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000077155:Granulins; C120204:Grn protein, mouse; C556062:IL10 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D016753:Interleukin-10; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate