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Immunol."],"abstract":"<jats:p>Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM<jats:sup>\u00ae<\/jats:sup> MarketScan<jats:sup>\u00ae<\/jats:sup> Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, <jats:italic>in vitro<\/jats:italic> experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of <jats:italic>MMP9<\/jats:italic> and <jats:italic>ACE2<\/jats:italic>, which are responsible for the pathophysiology of BP in monocytes\/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7\/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1084960","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T08:33:56Z","timestamp":1672907636000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor 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