TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases
Mirjam Schenk, … , Frank Seibold, Christoph Mueller
Mirjam Schenk, … , Frank Seibold, Christoph Mueller
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3097-3106. https://doi.org/10.1172/JCI30602.
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Research Article Inflammation

TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases

Abstract

Triggering receptor expressed on myeloid cells–1 (TREM-1) potently amplifies acute inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators. Here we demonstrate that TREM-1 is also crucially involved in chronic inflammatory bowel diseases (IBD). Myeloid cells of the normal intestine generally lack TREM-1 expression. In experimental mouse models of colitis and in patients with IBD, however, TREM-1 expression in the intestine was upregulated and correlated with disease activity. TREM-1 significantly enhanced the secretion of relevant proinflammatory mediators in intestinal macrophages from IBD patients. Blocking TREM-1 by the administration of an antagonistic peptide substantially attenuated clinical course and histopathological alterations in experimental mouse models of colitis. This effect was also seen when the antagonistic peptide was administered only after the first appearance of clinical signs of colitis. Hence, TREM-1–mediated amplification of inflammation contributes not only to the exacerbation of acute inflammatory disorders but also to the perpetuation of chronic inflammatory disorders. Furthermore, interfering with TREM-1 engagement leads to the simultaneous reduction of production and secretion of a variety of pro-inflammatory mediators such as TNF, IL-6, IL-8 (CXCL8), MCP-1 (CCL2), and IL-1β. Therefore, TREM-1 may also represent an attractive target for the treatment of chronic inflammatory disorders.

Authors

Mirjam Schenk, Axel Bouchon, Frank Seibold, Christoph Mueller

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Figure 6

Blocking TREM-1 attenuates intestinal inflammation in 2 distinct mouse models of colitis.

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Blocking TREM-1 attenuates intestinal inflammation in 2 distinct mouse m...
Colitis was induced either by the transfer of splenic CD4+CD45RBhi T cells into RAG2–/– recipients (top row) or by oral administration of DSS (bottom row). Upon colitis induction, experimental mice were treated daily either with an antagonistic TREM-1 peptide (LP17) or with a control peptide. (A) Fecal samples from each mouse were tested for the presence of occult blood and bloody diarrhea to obtain the stool consistency score (see Methods). Data are presented as mean ± SEM; n = 10. (B) The colon length of each mouse was measured from the end of the cecum to the anus; indicated are the mean loss of colon length (%) at the end of the experiment. (C) The colitis scores for the 2 groups (LP17-treated and control-treated) were determined as described in Methods. (D) PCR analysis for TREM-1 and TNF mRNA was performed on identical segments of the distal colon in untreated mice (RAG2–/–; C57BL/6 [B6]) and antagonistic TREM-1– (LP17-) and control peptide–treated mice upon colitis induction. β-Actin was used as loading control. Results for 1 representative unmanipulated control mouse and 2 representative experimental mice per group are shown. ***P < 0.001; n = 10.