Abstract
The expression of Triggering Receptor Expressed on Myeloid cells (TREM)-1 has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of TREM-1 specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment TREM-1 expression levels of CD14+ monocytes of Crohn’s disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low TREM-1 expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with TREM-1 expression levels in the CD patient cohort. In conclusion, our results indicate that TREM-1 expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of TREM-1.
Highlights
Despite the considerable efficacy of anti-Tumor Necrosis Factor (TNF)-a monoclonal antibody therapy in the treatment of inflammatory bowel disease (IBD), about one third of patients do not respond [1]
Pretreatment Triggering Receptor Expressed on Myeloid cells (TREM)-1 expression levels of CD14+ monocytes in peripheral blood of Crohn’s disease (CD) patients were predictive of outcome to anti-TNF monoclonal antibody (mAb) therapy, with low TREM-1 expression being associated with response to anti-TNF (Figure 1A)
The whole blood TREM-1 expression has been described as a predictive marker for anti-TNF mAb therapy responsiveness in patients with IBD [3, 9, 10] Interestingly, while both Gaujoux et al [3] and Verstockt et al [10] describe TREM-1 expression consistently being upregulated in intestinal biopsies of anti-TNF non-responders compared to anti-TNF responders, the high TREM-1 expression in whole blood was only found to associate with anti-TNF non-response in the study by Verstockt et al [10], in contrast to the study by Gaujoux et al [3] that showed exactly the opposite association
Summary
Despite the considerable efficacy of anti-Tumor Necrosis Factor (TNF)-a monoclonal antibody (mAb) therapy in the treatment of inflammatory bowel disease (IBD), about one third of patients do not respond [1]. The reason for this primary non-response is not entirely understood, the search for predictive markers has been hampered considerably [2]. Verstockt et al [9, 10] reported exactly the opposite, high whole blood TREM-1 levels predict anti-TNF non-responsiveness. The studies defined response to anti-TNF differently, the explanation for the opposite association with anti-TNF response was not completely clear
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