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 integri...
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Wiley
2023-04-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1233 |
| _version_ | 1797838662980861952 |
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| author | Katrin Sommer Karin Heidbreder Lucas Kreiss Mark Dedden Eva‐Maria Paap Maximilian Wiendl Emily Becker Raja Atreya Tanja M. Müller Imke Atreya Maximilian Waldner Sebastian Schürmann Oliver Friedrich Markus F. Neurath Sebastian Zundler |
| author_facet | Katrin Sommer Karin Heidbreder Lucas Kreiss Mark Dedden Eva‐Maria Paap Maximilian Wiendl Emily Becker Raja Atreya Tanja M. Müller Imke Atreya Maximilian Waldner Sebastian Schürmann Oliver Friedrich Markus F. Neurath Sebastian Zundler |
| author_sort | Katrin Sommer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:44:28Z |
| format | Article |
| id | doaj.art-ac3db3afc3cb4b44b45838ef0d030115 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-09T15:44:28Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-ac3db3afc3cb4b44b45838ef0d0301152023-04-27T05:12:30ZengWileyClinical and Translational Medicine2001-13262023-04-01134n/an/a10.1002/ctm2.1233Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healingKatrin Sommer0Karin Heidbreder1Lucas Kreiss2Mark Dedden3Eva‐Maria Paap4Maximilian Wiendl5Emily Becker6Raja Atreya7Tanja M. Müller8Imke Atreya9Maximilian Waldner10Sebastian Schürmann11Oliver Friedrich12Markus F. Neurath13Sebastian Zundler14Department of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyInstitute of Medical Biotechnology Department of Chemical and Biological Engineering (CBI) Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyDepartment of Medicine University Hospital Erlangen and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen GermanyAbstract 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.https://doi.org/10.1002/ctm2.1233etrolizumabgut homingintestinal wound healingmonocytesvedolizumab |
| spellingShingle | Katrin Sommer Karin Heidbreder Lucas Kreiss Mark Dedden Eva‐Maria Paap Maximilian Wiendl Emily Becker Raja Atreya Tanja M. Müller Imke Atreya Maximilian Waldner Sebastian Schürmann Oliver Friedrich Markus F. Neurath Sebastian Zundler Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing Clinical and Translational Medicine etrolizumab gut homing intestinal wound healing monocytes vedolizumab |
| title | Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing |
| title_full | Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing |
| title_fullStr | Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing |
| title_full_unstemmed | Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing |
| title_short | Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing |
| title_sort | anti β7 integrin treatment impedes the recruitment on non classical monocytes to the gut and delays macrophage mediated intestinal wound healing |
| topic | etrolizumab gut homing intestinal wound healing monocytes vedolizumab |
| url | https://doi.org/10.1002/ctm2.1233 |
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