HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge

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.

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion

“…Examining the importance of HDAC6 in vivo in a CF context, we demonstrated that depletion of Hdac6 expression from a CF mouse model increased CF mouse linear growth, increased weight gain, and restored the ability to store fat 22 . We also demonstrated the depletion of Hdac6 in CF mice normalizes the inflammatory response and the ability to clear bacteria in a murine airway infection model 23 . The restoration of linear growth and the increase in insulin-like growth factor-1 (IGF-1) in CF mice lacking Hdac6 expression suggests that the hypothalamus-pituitary axis is being affected by Hdac6 depletion indicating a direct neurological impact 24,25 .…”

“…Inflammation has been correlated with depression in a number of studies 35 – 38 , therefore, alleviating inflammatory signaling may be a mode of action of Hdac6 depletion. We have shown specifically in CF mouse models that depletion of Hdac6 results in reduced inflammation and better clearance of bacteria in airways from infected mice 23 . Several studies have demonstrated the anti-inflammatory benefits of HDAC6 inhibition, with two specifically looking at neuronal inflammation.…”

“…It has been shown that CF mouse models also exhibit anxiety-like behavior qualities suggesting that there is a biological, mechanistic reason for behavior manifestations in addition to the stresses of chronic disease that can contribute to anxiety and depression 13 . We have previously demonstrated that depletion of Hdac6 expression in CF mice improve responses to bacterial challenge as well as growth to more WT levels 22,23 . Growth restoration included both increased weight gain due to increased fat deposition, but also improved linear growth 22 .…”

“…Dissociation of Gα s from lipid rafts also occurs with other known anti-depressants through different mechanisms 35 . Another potential mechanism of action is the anti-inflammatory effect of HDAC6 inhibition 23 . Inflammation has been correlated with depression in a number of studies 35 – 38 , therefore, alleviating inflammatory signaling may be a mode of action of Hdac6 depletion.…”

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

“…The treatment of CF patients, carrying at least one copy of the G551D mutation, with Ivacaftor leads to reduced migration and activation of neutrophils [129], as well as improved bacterial clearance in this cohort of patients [127]. Another potential therapeutic target for CF was proposed to be histone deacetylase 6 (HDAC6), as its depletion, in a mouse model, reduced the recruitment of neutrophils to the lungs, followed by an improved response to infection and an increased rate of bacterial clearance and reduced weight loss [130].…”