Sommer K, Heidbreder K, Kreiß L, Dedden M, Paap EM, Wiendl M, Becker E, Atreya R, Müller T, Atreya I, Waldner M, Schürmann S, Friedrich O, Neurath M, Zundler S (2023)
Publication Type: Journal article, Original article
Publication year: 2023
Book Volume: 13
Journal Issue: 4
DOI: 10.1002/ctm2.1233
BackgroundClosing 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-alpha 4 beta 7 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-beta 7 antibody etrolizumab on wound healing are unclear so far. MethodsWe 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 multi-photon 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. ResultsHuman and mouse non-classical monocytes expressed more alpha E beta 7 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. ConclusionsCombined blockade of alpha E beta 7 and alpha 4 beta 7 with etrolizumab seems to exceed the effect of anti-alpha 4 beta 7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.
APA:
Sommer, K., Heidbreder, K., Kreiß, L., Dedden, M., Paap, E.-M., Wiendl, M.,... Zundler, S. (2023). Anti-beta 7 integrin treatment impedes the recruitment on non-classical monocytes to the gut and delays macrophage-mediated intestinal wound healing. Clinical and Translational Medicine, 13(4). https://dx.doi.org/10.1002/ctm2.1233
MLA:
Sommer, Katrin, et al. "Anti-beta 7 integrin treatment impedes the recruitment on non-classical monocytes to the gut and delays macrophage-mediated intestinal wound healing." Clinical and Translational Medicine 13.4 (2023).
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