HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge

Julie Rosenjack,Rebecca J Darrah,Thomas J Kelley,Craig A Hodges

doi:10.1038/s41598-019-46555-4

Julie Rosenjack, Rebecca J Darrah + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-46555-4

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Journal: Scientific Reports	Publication Date: Jul 16, 2019
Citations: 21	License type: open-access

Affiliation: Case Western Reserve University

Abstract

The hypothesis of this study was that Hdac6 depletion would restore cystic fibrosis (CF) responses to bacterial challenge to more wild type profiles using a CF mouse model. CF mice harboring the F508del Cftr mutation respond to bacterial challenge with 25,000 CFU Pseudomonas aeruginosa embedded into agarose beads to slow clearance. CF mice respond significantly more aggressively to this challenge compared to WT mice with respect to bacterial clearance, weight loss, neutrophil recruitment, and MIP-2 production. Depletion of Hdac6 expression in the CF mice (CF/Hdac6) significantly improves these responses to more WT levels. Weight loss in response to infection is most severe in CF mice and significantly attenuated in CF/Hdac6 mice. Bacterial levels are reduced at a faster rate in CF/Hdac6 mice compared to CF mice where infection persists. Percent neutrophils in lung lavage fluid post-infection are significantly higher in CF mice, but returned to WT levels with CF/Hdac6 mice. Similarly, CF Mip-2 levels are restored to WT levels in the absence of Hdac6 expression. These data demonstrate that Hdac6 depletion restores CF responses to bacterial challenge to WT-like profiles and offer a potential therapeutic avenue for addressing inflammation and infection in CF airways independently of Cftr correction.

Highlights

Understanding the cystic fibrosis (CF) inflammatory response is an important goal in CF research despite recent advances and success of CFTR-targeted therapies
To address the endosomal trafficking impairment in CF cells, we found that trafficking can be restored by increasing tubulin acetylation through inhibition of histone deacetylase 6 (HDAC6), a cytosolic deacetylase that targets tubulin[4]
We investigated the effects of infection with a clinical isolate of Pseudomonas aeruginosa in the CF/ Hdac[6] mouse model

Summary

Introduction

Understanding the CF inflammatory response is an important goal in CF research despite recent advances and success of CFTR-targeted therapies. Restoring proper responses to inflammatory stimuli would still allow for a protective immune response but have a lower risk of dangerous immune suppression Key to this approach is identifying key regulatory changes in CF that control a number of CF phenotypes that can be therapeutically targeted. Our previous work has identified two primary alterations to microtubule regulation associated with CF4,6 The first of these alterations is slowed microtubule reformation rates after depolymerization in CF primary human nasal epithelial (HNE) cells compared to control non-CF HNE cells[5,6]. This phenotype can be restored with adenosine monophosphate activated protein kinase (AMPK) activators and we have shown that restoration of microtubule formation by ibuprofen may be part of the mechanism of its efficacy[6]. HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in a CF mouse model where inflammation was stimulated by Pseudomonas aeruginosa lipopolysaccharide (Pa-LPS) exposure[11]

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