A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice.

Abstract

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.

• Authors: Shireen Mohammad, Sura Al Zoubi, Debora Collotta, Nadine Krieg, Bianka Wissuwa, Gustavo Ferreira Alves, Gareth S D Purvis, Giuseppe Danilo Norata, Andrea Baragetti, Alberico Luigi Catapano, Egle Solito, Elisabeth Zechendorf, Tobias Schürholz, Wilmar Correa-Vargas, Klaus Brandenburg, Sina M Coldewey, Massimo Collino, Muhammad M Yaqoob, Lukas Martin, Christoph Thiemermann
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 701275 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 34349763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Mohammad, Al Zoubi, Collotta, Krieg, Wissuwa, Ferreira Alves, Purvis, Norata, Baragetti, Catapano, Solito, Zechendorf, Schürholz, Correa-Vargas, Brandenburg, Coldewey, Collino, Yaqoob, Martin and Thiemermann.

Chemical References

• Antimicrobial Cationic Peptides
• Antimicrobial Peptides
• Lipopolysaccharides
• Cathelicidins

Topics

• Animals
• Antimicrobial Cationic Peptides (metabolism)
• Antimicrobial Peptides (pharmacology)
• Diabetes Mellitus, Type 2 (metabolism)
• Diet, High-Fat (adverse effects)
• Endotoxemia (etiology, metabolism)
• Humans
• Inflammation (etiology, metabolism)
• Lipopolysaccharides (antagonists & inhibitors)
• Male
• Mice
• Mice, Inbred C57BL
• Cathelicidins