CD137 Facilitates the Resolution of Acute DSS-Induced Colonic Inflammation in Mice

Julia M Martínez Gómez,Herbert Schwarz,Lieping Chen,Thomas Karrasch,David L Boone

doi:10.1371/journal.pone.0073277

Julia M Martínez Gómez, Herbert Schwarz + Show 3 more

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https://doi.org/10.1371/journal.pone.0073277

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Abstract

BackgroundCD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. Expression of CD137 is upregulated in the lamina propria cells of Crohn’s disease patients. Here, the role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined.MethodsWe induced acute large bowel inflammation (colitis) via DSS administration in CD137−/− and wild-type (WT) mice. Colitis severity was evaluated by clinical parameters (weight loss), cytokine secretion in colon segment cultures, and scoring of histological inflammatory parameters. Additionally, populations of lamina propria mononuclear cells (LPMNC) and intraepithelial lymphocytes (IEL) were characterized by flow cytometry. In a subset of mice, resolution of intestinal inflammation was evaluated 3 and 7 days after withdrawal of DSS.ResultsWe found that both CD137−/− and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure. However, the resolution of colonic inflammation was impaired in the absence of CD137. This was accompanied by a higher histological score of inflammation, and increased release of the pro-inflammatory mediators granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL1, IL-17 and IFN-γ. Further, there were significantly more neutrophils among the LPMNC of CD137−/− mice, and reduced numbers of macrophages among the IEL.ConclusionWe conclude that CD137 plays an essential role in the resolution of acute DSS-induced intestinal inflammation in mice.

Highlights

CD137 (TNFRS9, 4-1BB) is a member of the tumor necrosis factor (TNF) receptor family, and CD137 ligand (CD137L) is a member of the TNF superfamily
TNF has been demonstrated to play a key role in human inflammatory bowel diseases (IBD) [11,12,13] and in experimental models of autoimmune colitis in mice [14,15], where TNF induces intestinal epithelial cell apoptosis during intestinal inflammation, thereby aggravating the disease [16]
We found that while both CD1372/2 and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure, the resolution of colonic inflammation was significantly impaired in CD1372/2 mice

Summary

Introduction

CD137 (TNFRS9, 4-1BB) is a member of the tumor necrosis factor (TNF) receptor family, and CD137 ligand (CD137L) is a member of the TNF superfamily. CD137 and its ligand are expressed mostly on immune cells, and the CD137 receptor/ ligand system regulates activation, proliferation, differentiation and cell death of leukocytes [1,2,3,4]. CD137 is expressed activation-dependently on T cells, where it acts as a potent costimulatory molecule [5]. TNF has been demonstrated to play a key role in human IBD [11,12,13] and in experimental models of autoimmune colitis in mice [14,15], where TNF induces intestinal epithelial cell apoptosis during intestinal inflammation, thereby aggravating the disease [16]. CD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. The role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined

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