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

Abstract

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.

Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder

“…7 ). Our results suggest that psoriasin in addition to other factors demonstrated by us 67 as well as others 17 , 34 aim to outcompete the negative consequences of high glucose. We hypothesize that these factors although partly acting independently may still be interrelated thereby strengthening the effect.…”

Cathelicidin Antimicrobial Peptide Levels in Atherosclerosis and Myocardial Infarction in Mice and Human

“…Mohanty et al demonstrated that activation of hypoxia-inducible factor 1 (HIF-1) enhanced Cramp gene expression [ 28 ]. Furthermore, higher levels of proinflammatory cytokines and CAMP correlate with HIF-1 in type 2 diabetic patients [ 28 ].…”

“…Mohanty et al demonstrated that activation of hypoxia-inducible factor 1 (HIF-1) enhanced Cramp gene expression [ 28 ]. Furthermore, higher levels of proinflammatory cytokines and CAMP correlate with HIF-1 in type 2 diabetic patients [ 28 ]. Since myocardial infarction results in hypoxemia [ 3 ], hypoxic effects might also play a role in modulating circulating CAMP/CRAMP levels in our experimental models.…”

The Effect of Oral Administration of the Antibacterial Peptide MPX on Intestinal Inflammation of Mice in Experimental Infection with Escherichia Coli Strain O157: H7

“…Studies have found that antimicrobial peptide LL-37 not only has anti-inflammatory effects, but also increases the expression of pro-inflammatory factors under certain conditions. For example, the expression of IL-8 in macrophages and IL-6 in dendritic cells may be enhanced by the peptide LL-37(Mohanty et al, 2021). Peptides such as defensins, LFP-20 inhibits the NF-κB signalling pathway and reduces inflammation (Rodriguez-Carlos et al, 2021;Zong et al, 2015).…”