Dataset Information

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

ABSTRACT:

Introduction

Macrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood.

Methods

Taking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence.

Results

We show that wound healing in Nr4a1-deficient mice is substantially delayed and associated with reduced peri-lesional presence of macrophages with a wound healing phenotype.

Discussion

Our data suggest that non-classical monocytes are biased towards wound healing macrophages. These insights might help to understand, how targeting monocyte recruitment to the intestine can be used to modulate intestinal macrophage functions.

SUBMITTER: Heidbreder K

PROVIDER: S-EPMC9890957 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

Heidbreder Karin K Sommer Katrin K Wiendl Maximilian M Müller Tanja M TM Atreya Imke I Hildner Kai K Neurath Markus F MF Zundler Sebastian S

Frontiers in immunology 20230118

<h4>Introduction</h4>Macrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood.<h4>Methods</h4>Taking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence.<h4>Results</h4>We s ...[more]

PMID: 36741412

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Project description: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-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.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 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.ConclusionsCombined 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.

Dataset Information

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

Introduction

Methods

Results

Discussion

Publications

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

Similar Datasets

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