CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution
Ulcerative colitis (UC) is a multifactorial condition characterized by a destructive immune response that failed to be attenuated by common regulatory mechanisms which reduce inflammation and promote mucosa healing. The inhibition of CD26, a multifunctional glycoprotein that controls the immune resp...
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2022-05-01
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author | Iva Vukelic Suncica Buljevic Lara Baticic Karmela Barisic Barbara Franovic Dijana Detel |
author_facet | Iva Vukelic Suncica Buljevic Lara Baticic Karmela Barisic Barbara Franovic Dijana Detel |
author_sort | Iva Vukelic |
collection | DOAJ |
description | Ulcerative colitis (UC) is a multifactorial condition characterized by a destructive immune response that failed to be attenuated by common regulatory mechanisms which reduce inflammation and promote mucosa healing. The inhibition of CD26, a multifunctional glycoprotein that controls the immune response via its dipeptidyl peptidase (DP) 4 enzyme activity, was proven to have beneficial effects in various autoimmune inflammatory diseases. The polarization of macrophages into either pro-inflammatory M1 or anti-inflammatory M2 subclass is a key intersection that mediates the immune-inflammatory process in UC. Hence, we hypothesized that the deficiency of CD26 affects that process in the dextran sulfate sodium (DSS)-induced model of UC. We found that mRNA expression of M2 markers arginase 1 and Fizz were increased, while the expression of M1 marker inducible NO synthase was downregulated in CD26<sup>−/−</sup> mice. Decreased STAT1 mRNA, as well as upregulated pSTAT6 and pSTAT3, additionally support the demonstrated activation of M2 macrophages under CD26 deficiency. Finally, we investigated DP8 and DP9, proteins with DP4-like activity, and found that CD26 deficiency is not a key factor for the noted upregulation of their expression in UC. In conclusion, we demonstrate that CD26 deficiency regulates macrophage polarization toward the anti-inflammatory M2 phenotype, which is driven by STAT6/STAT3 signaling pathways. This process is additionally enhanced by the reduction of M1 differentiation via the suppression of proinflammatory STAT1. Therefore, further studies should investigate the clinical potential of CD26 inhibitors in the treatment of UC. |
first_indexed | 2024-03-10T03:45:00Z |
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issn | 1661-6596 1422-0067 |
language | English |
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spelling | doaj.art-fd3c9a55b745401fbaf3cc6d4b647f332023-11-23T11:23:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310550610.3390/ijms23105506CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and ResolutionIva Vukelic0Suncica Buljevic1Lara Baticic2Karmela Barisic3Barbara Franovic4Dijana Detel5Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, CroatiaDepartment of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, CroatiaDepartment of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, CroatiaDepartment of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, 10000 Zagreb, CroatiaDepartment of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, CroatiaDepartment of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, CroatiaUlcerative colitis (UC) is a multifactorial condition characterized by a destructive immune response that failed to be attenuated by common regulatory mechanisms which reduce inflammation and promote mucosa healing. The inhibition of CD26, a multifunctional glycoprotein that controls the immune response via its dipeptidyl peptidase (DP) 4 enzyme activity, was proven to have beneficial effects in various autoimmune inflammatory diseases. The polarization of macrophages into either pro-inflammatory M1 or anti-inflammatory M2 subclass is a key intersection that mediates the immune-inflammatory process in UC. Hence, we hypothesized that the deficiency of CD26 affects that process in the dextran sulfate sodium (DSS)-induced model of UC. We found that mRNA expression of M2 markers arginase 1 and Fizz were increased, while the expression of M1 marker inducible NO synthase was downregulated in CD26<sup>−/−</sup> mice. Decreased STAT1 mRNA, as well as upregulated pSTAT6 and pSTAT3, additionally support the demonstrated activation of M2 macrophages under CD26 deficiency. Finally, we investigated DP8 and DP9, proteins with DP4-like activity, and found that CD26 deficiency is not a key factor for the noted upregulation of their expression in UC. In conclusion, we demonstrate that CD26 deficiency regulates macrophage polarization toward the anti-inflammatory M2 phenotype, which is driven by STAT6/STAT3 signaling pathways. This process is additionally enhanced by the reduction of M1 differentiation via the suppression of proinflammatory STAT1. Therefore, further studies should investigate the clinical potential of CD26 inhibitors in the treatment of UC.https://www.mdpi.com/1422-0067/23/10/5506ulcerative colitisdipeptidyl peptidase 4CD26 deficiencymacrophage polarizationSTAT molecules |
spellingShingle | Iva Vukelic Suncica Buljevic Lara Baticic Karmela Barisic Barbara Franovic Dijana Detel CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution International Journal of Molecular Sciences ulcerative colitis dipeptidyl peptidase 4 CD26 deficiency macrophage polarization STAT molecules |
title | CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution |
title_full | CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution |
title_fullStr | CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution |
title_full_unstemmed | CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution |
title_short | CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution |
title_sort | cd26 deficiency controls macrophage polarization markers and signal transducers during colitis development and resolution |
topic | ulcerative colitis dipeptidyl peptidase 4 CD26 deficiency macrophage polarization STAT molecules |
url | https://www.mdpi.com/1422-0067/23/10/5506 |
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