Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing

Abstract

Background Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte‐derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti‐α4β7 integrin antibody vedolizumab blocks the recruitment of non‐classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti‐β7 antibody etrolizumab on wound healing are unclear so far. Methods We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound‐associated monocyte recruitment dynamics with multiphoton microscopy and compared the effects of etrolizumab and vedolizumab surrogate (‐s) antibodies on experimental wound healing and wound‐associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab. Results Human and mouse non‐classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab‐s, which blocked non‐classical monocyte adhesion to MAdCAM‐1 and E‐Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab‐s along with a reduction of peri‐lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down‐regulated on treatment with etrolizumab, but not with placebo. Conclusions Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti‐α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.

The association between circulating leukocytes and inflammatory bowel disease: a two-sample Mendelian randomization study

“…The possible mechanism of action for nonclassical monocytes is associated with adhesion, production of complement components, and Fcγ-mediated phagocytosis. During the development of IBD, the intestinal epithelial barrier is compromised, allowing microbes to enter the tissue ( 33 ). Non-classical monocytes are recruited to the gut via α4β7 integrin, which transforms into macrophages and promotes wound healing ( 34 , 35 ).…”

Origin and Function of Monocytes in Inflammatory Bowel Disease

“…89 Moreover, it has been observed that non-classical monocytes tend to differentiate into macrophages that play a pivotal role in promoting wound healing. 90,91 Over time, monocytes also possess the capacity to differentiate into migratory antigen-presenting cells with dendritic cell characteristics, referred to as moDCs. 47 Consequently, within the inflammatory milieu of IBD, monocytes differentiation emerges as a complex and multifaceted process.…”