Inflammatory disorders: Chronically amplifying disease

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Triggering receptor expressed on myeloid cells 1 (TREM1) has a pathogenic role in chronic inflammatory disorders and may be a therapeutic target for the treatment of inflammatory bowel disease.

Triggering receptor expressed on myeloid cells 1 (TREM1) is involved in the amplification of acute inflammatory responses. Now, writing in the Journal of Clinical Investigation, Mueller and colleagues reveal that TREM1 also has a pathogenic role in chronic inflammatory disorders, and demonstrate the therapeutic potential of TREM1 blockade in the treatment of inflammatory bowel diseases (IBDs).


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TREM1, a member of the immunoglobulin superfamily, is constitutively expressed on most monocytes, macrophages and neutrophils. Its upregulation following stimulation with lipopolysaccharide, bacteria or fungi, resulting in enhanced production of pro-inflammatory mediators such as tumour necrosis factor (TNF), monocyte chemoattractant protein 1 (MCP1) and interleukin 8 (IL8), led to the identification of its role in acute inflammatory diseases.

In agreement with this role, the authors first identified a striking upregulation in the number of TREM1-positive macrophages in the inflamed intestine of patients with acute inflammatory diseases, appendicitis and acute diverticulitis — with expression being almost absent in normal healthy intestine.

This finding prompted the authors to also investigate TREM1 expression in chronic inflammatory diseases of the intestine. To their surprise, they found a fivefold elevation in TREM1 levels in affected lesions in patients with chronic IBDs, ulcerative colitis and Crohn's disease.

To assess the potential consequence of this elevation, they isolated macrophages from the inflamed intestine of patients and exposed them to an agonistic TREM1-binding antibody. This further amplified the secretion of various pro-inflammatory mediators, including TNF, MCP1, IL6, IL8 and IL1 beta — effects that are likely to contribute to disease exacerbation and tissue destruction.

Further studies identified a clear association of TREM1 with disease status. High TREM1 levels were only observed in affected intestinal segments from patients with active ulcerative colitis or Crohn's disease, and not in unaffected tissue samples or in patients harbouring inactive disease. Furthermore, in two different mouse models of colitis, TREM1 was upregulated at a very early stage following disease induction, preceding the first histopathological signs of colitis. Increased Trem1 expression also correlated closely with enhanced disease activity. TREM1 may therefore represent a reliable marker to assess IBD activity.

Finally, to explore the possibility of therapeutically targeting TREM1, mice were treated with an antagonistic synthetic peptide (Lp17) — derived from the extracellular domain of TREM1 — upon induction of colitis. Lp17 clearly reduced the histopathological alterations and symptoms associated with colitis, in conjunction with a dramatic decrease of TREM1 and TNF in the affected colon. Similar effects of Lp17 were also observed in mice with overt colitis, confirming TREM1 as an attractive target for the treatment of IBD. As TREM1 blockade results in a robust attenuation of inflammatory responses, this strategy may have applications in the treatment of other chronic inflammatory disorders.

Sarah Crunkhorn

References

Schenk, M. et al. TREM-1-expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J. Clin. Invest. 117, 3097–3106 (2007) | Article | PubMed |