HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.

Autor: Mohanty S; Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden., Kamolvit W; Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden.; Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand., Zambrana S; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Area de Farmacologia, Facultad de Ciencias Farmacéuticas Y Bioquimicas, Instituto de Investigaciones Farmaco Bioquimicas, Universidad Mayor de San Andres, La Paz, Bolivia., Gonzales E; Area de Farmacologia, Facultad de Ciencias Farmacéuticas Y Bioquimicas, Instituto de Investigaciones Farmaco Bioquimicas, Universidad Mayor de San Andres, La Paz, Bolivia., Tovi J; Capio Health Care Center, Solna, Sweden., Brismar K; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Östenson CG; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Brauner A; Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden. Annelie.Brauner@ki.se.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2022 Jan; Vol. 100 (1), pp. 101-113. Date of Electronic Publication: 2021 Oct 15.
DOI: 10.1007/s00109-021-02134-7
Abstrakt: Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. KEY MESSAGES: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.
(© 2021. The Author(s).)
Databáze: MEDLINE
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