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

Fanhua Wei; Yuying Zhang; Jinlong Jian; Jyoti Joshi Mundra; Qingyun Tian; Jiqiang Lin; Juan Jose Lafaille; Wei Tang; Weiming Zhao; Xiuping Yu; Chuan-Ju Liu

doi:10.1038/srep07023

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

Sci Rep. 2014 Nov 12:4:7023. doi: 10.1038/srep07023.

Authors

Affiliations

¹ 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.
² Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003.
³ Department of Pathology, New York University Medical Center, New York, NY, 10016.
⁴ Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012.
⁵ 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.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Bone Marrow / immunology
Bone Marrow / pathology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / pathology
Dextran Sulfate
Disease Models, Animal
Disease Progression
Gene Expression Regulation
Granulins
Humans
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 / deficiency
Interleukin-10 / genetics*
Mice
Mice, Knockout
Progranulins
Receptors, Tumor Necrosis Factor, Type II / deficiency
Receptors, Tumor Necrosis Factor, Type II / genetics*
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Recombinant Proteins / pharmacology
Signal Transduction
Transplantation Chimera
Trinitrobenzenesulfonic Acid

Substances

Anti-Inflammatory Agents, Non-Steroidal
Granulins
Grn protein, mouse
IL10 protein, mouse
Intercellular Signaling Peptides and Proteins
Progranulins
Receptors, Tumor Necrosis Factor, Type II
Recombinant Proteins
Interleukin-10
Trinitrobenzenesulfonic Acid
Dextran Sulfate

Abstract

Publication types

MeSH terms

Substances

Grants and funding