Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge

Abstract

Antimicrobial peptides (AMP) are defense effectors of the innate immunity playing a crucial role in the intestinal homeostasis with commensals and protection against pathogens. Herein we aimed to investigate AMP gene regulation by deciphering specific characteristics allowing their enhanced expression among innate immune genes, particularly those encoding proinflammatory mediators. Our emphasis was on epigenetic regulation of the gene encoding the AMP β-defensin 2 (HBD2), taken as a model of possibly specific induction, upon challenge with a commensal bacterium, compared with the proinflammatory cytokine IL-8. Using an in vitro model of colonic epithelial cells challenged with Escherichia coli K12, we showed that inhibition of histone deacetylases (HDAC) by trichostatin A dramatically enhanced induction of HBD2 expression, without affecting expression of IL-8. This mechanism was supported by an increased phosphorylation of histone H3 on serine S10, preferentially at the HBD2 promoter. This process occurred through activation of the IκB kinase complex, which also led to activation of NF-κB. Moreover, we demonstrated that NF-κB was modified by acetylation upon HDAC inhibition, partly by the histone acetyltransferase p300, and that both NF-κB and p300 supported enhanced induction of HBD2 expression. Furthermore, we identified additional genes belonging to antimicrobial defense and epithelial restitution pathways that showed a similar pattern of epigenetic control. Finally, we confirmed our finding in human colonic primary cells using an ex vivo organoid model. This work opens the way to use epigenetic pharmacology to achieve induction of epithelial antimicrobial defenses, while limiting the deleterious risk of an inflammatory response.

Loss of HDAC6 alters gut microbiota and worsens obesity

“…Whether this is due to immunologic or metabolic shifts, such as changes in bile acid biosynthesis, must be considered in future studies. That HDAC6 affects regulation of antimicrobial peptides (13,74) implies that innate immunity also may be involved. The commonality between early-life male and female pups showed that the later differences did not originate from inheritance of different bacterial communities.…”

Histone Deacetylase Inhibitors Reduce the Number of Herpes Simplex Virus-1 Genomes Initiating Expression in Individual Cells

“…Thus, the increase in expression of PML and ATRX we observed following HDACi treatment may reflect a specific regulation of this part of the immune response. Interestingly, inhibition of HDAC by TSA dramatically enhanced induction of antimicrobial peptides but not of proinflammatory cytokines (Fischer et al, 2016), further indicating selective expression post HDACi treatment of different parts of the immune system.…”

Epigenetic Mechanisms Regulate Innate Immunity against Uropathogenic and Commensal-Like Escherichia coli in the Surrogate Insect Model Galleria mellonella

“…Histone acetylation induces the expression of innate-immunity genes encoding products such as AMPs (but not inflammatory cytokines) in cells challenged with E. coli (42). We found that insects can selectively express AMPs and cytokine-like proteins when challenged with UPEC and ABU strains.…”