Efficacy of selective histone deacetylase 6 inhibition in mouse models of Pseudomonas aeruginosa infection: A new glimpse for reducing inflammation and infection in cystic fibrosis

Brindisi, Margherita; Barone, Simona; Rossi, Alice S.; Cassese, E; Gaudio, Nunzio Del; Morel, Álvaro Javier Feliz; Filocamo, Gessica; Alberico, Alessia; Fino, Ida De; Gugliandolo, Davide; Babaei, Mehrad; Bove, Guglielmo; Croce, Martina; Montesano, Camilla; Altucci, Lucia; Bragonzi, Alessandra; Summa, Vincenzo

doi:10.1016/j.ejphar.2022.175349

Cited by 4 publications

(5 citation statements)

References 63 publications

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“…Moreover, Hdac6 depletion limited weight loss and modulated neutrophil recruitment, further validating the benefits of HDAC6-selective inhibitors in diseases featuring chronic airway inflammation, such as CF (Rosenjack et al, 2019). We recently confirmed these data through pharmacological inhibition of HDAC6, demonstrating for the first time the efficacy in reducing bacterial load and inflammatory markers in a mouse model of chronic P. aeruginosa infection (Brindisi et al, 2022).…”

Section: Graphical Abstractsupporting

confidence: 60%

Unveiling the modulation of Pseudomonas aeruginosa virulence and biofilm formation by selective histone deacetylase 6 inhibitors

Barone,

Mateu,

Turco

et al. 2024

Front. Microbiol.

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Bacterial infections represent a key public health issue due to the occurrence of multidrug-resistant bacteria. Recently, the amount of data supporting the dynamic control of epigenetic pathways by environmental cues has triggered research efforts toward the clarification of their role in microbial infections. Among protein post-translational modifications, reversible acetylation is the most implicated in the feedback to environmental stimuli and in cellular homeostasis. Accordingly, the latest studies identified the histone deacetylase 6 (HDAC6) enzyme as a crucial player in the complex molecular machinery underlying bacterial clearance or killing. A very important milestone for the elucidation of the consequence of HDAC6 activity in bacterial infections is herein described, unveiling for the first time the role of a potent HDAC6 inhibitor in interfering with biofilm formation and modulating virulence factors of P. aeruginosa. We demonstrated that compound F2F-2020202 affected the production of some important virulence factors in P. aeruginosa, namely pyocyanin and rhamnolipids, clearly impairing its ability to form biofilm. Furthermore, evidence of possible QS involvement is supported by differential regulation of specific genes, namely RhlI, phAz1, and qsrO. The data herein obtained also complement and in part explain our previous results with selective HDAC6 inhibitors able to reduce inflammation and bacterial load in chronic infection models recapitulating the cystic fibrosis (CF) phenotype. This study fosters future in-depth investigation to allow the complete elucidation of the molecular mechanisms underlying HDAC6’s role in bacterial infections.

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Section: Graphical Abstractsupporting

confidence: 60%

Unveiling the modulation of Pseudomonas aeruginosa virulence and biofilm formation by selective histone deacetylase 6 inhibitors

Barone,

Mateu,

Turco

et al. 2024

Front. Microbiol.

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“…involved in the proinflammatory response to infection [83]. More research has shown that trained immunity can be induced by non-specific stimuli, such as exposure to microbial components like OMVs [22,23].…”

Section: Omvs Alter the Host Immune Response To Subsequent Bacterial ...mentioning

confidence: 99%

“…Epigenetic reprogramming by bacterial infections extends beyond in vitro studies and has been demonstrated in an in vivo murine infection model. Brindisi et al reported a significant reduction in proinflammatory cytokines in the CF mouse lung following P. aeruginosa infection, achieved by using a chemical inhibitor that targets histone deacetylase 6 (HDAC6), a major player in CF proinflammatory phenotype dysregulation [ 83 ]. By inhibiting HDAC6 activity and consequently increasing histone acetylation, the authors successfully demonstrated a notable reduction in interleukins and chemokines involved in the proinflammatory response to infection [ 83 ].…”

Section: Omvs Alter the Host Immune Response To Subsequent Bacterial ...mentioning

confidence: 99%

“…Brindisi et al reported a significant reduction in proinflammatory cytokines in the CF mouse lung following P. aeruginosa infection, achieved by using a chemical inhibitor that targets histone deacetylase 6 (HDAC6), a major player in CF proinflammatory phenotype dysregulation [ 83 ]. By inhibiting HDAC6 activity and consequently increasing histone acetylation, the authors successfully demonstrated a notable reduction in interleukins and chemokines involved in the proinflammatory response to infection [ 83 ]. More research has shown that trained immunity can be induced by non-specific stimuli, such as exposure to microbial components like OMVs [ 22 , 23 ].…”

Section: Omvs Alter the Host Immune Response To Subsequent Bacterial ...mentioning

confidence: 99%

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Bacterial Outer Membrane Vesicles and Immune Modulation of the Host

Charpentier,

Dolben,

Hendricks

et al. 2023

Membranes

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This article reviews the role of outer membrane vesicles (OMVs) in mediating the interaction between Gram-negative bacteria and their human hosts. OMVs are produced by a diverse range of Gram-negative bacteria during infection and play a critical role in facilitating host–pathogen interactions without requiring direct cell-to-cell contact. This article describes the mechanisms by which OMVs are formed and subsequently interact with host cells, leading to the transport of microbial protein virulence factors and short interfering RNAs (sRNA) to their host targets, exerting their immunomodulatory effects by targeting specific host signaling pathways. Specifically, this review highlights mechanisms by which OMVs facilitate chronic infection through epigenetic modification of the host immune response. Finally, this review identifies critical knowledge gaps in the field and offers potential avenues for future OMV research, specifically regarding rigor and reproducibility in OMV isolation and characterization methods.

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“…In this study, treatment of Cftr +/+ or Cftr −/− mice with SAHA resulted in changes in interleukin-6 (IL-6) levels, nuclear factor kappa B (NFκB)-mediated signaling and neutrophil chemotaxis/activation. In another study [ 21 ], the efficiency of HDAC6 inhibitor, which was identified by screening patents and research papers was evaluated in the mouse model of P. aeruginosa acute and chronic respiratory infection. It was shown that inhibition of HDAC activity resulted in the reduction of several inflammatory interleukins, chemokines, growth factors, and interferon gamma (IFN-γ).…”

Section: Cystic Fibrosismentioning

confidence: 99%

Deacetylation of Histones and Non-histone Proteins in Inflammatory Diseases and Cancer Therapeutic Potential of Histone Deacetylase Inhibitors

Man,

Evran

2023

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Epigenetic changes play an important role in the pathophysiology of autoimmune diseases such as allergic asthma, multiple sclerosis, lung diseases, diabetes, cystic fibrosis, atherosclerosis, rheumatoid arthritis, and COVID-19. There are three main classes of epigenetic alterations: post-translational modifications of histone proteins, control by non-coding RNA and DNA methylation. Since histone modifications can directly affect chromatin structure and accessibility, they can regulate gene expression levels. Abnormal expression and activity of histone deacetylases (HDACs) have been reported in immune mediated diseases. Increased acetylated levels of lysine residues have been suggested to be related to the overexpression of inflammatory genes. This review focuses on the effect of HDAC modifications on histone and non–histone proteins in autoimmune diseases. Furthermore, we discuss the potential therapeutic effect of HDAC inhibitors (HDACi) used in these diseases.

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Efficacy of selective histone deacetylase 6 inhibition in mouse models of Pseudomonas aeruginosa infection: A new glimpse for reducing inflammation and infection in cystic fibrosis

Cited by 4 publications

References 63 publications

Unveiling the modulation of Pseudomonas aeruginosa virulence and biofilm formation by selective histone deacetylase 6 inhibitors

Unveiling the modulation of Pseudomonas aeruginosa virulence and biofilm formation by selective histone deacetylase 6 inhibitors

Bacterial Outer Membrane Vesicles and Immune Modulation of the Host

Deacetylation of Histones and Non-histone Proteins in Inflammatory Diseases and Cancer Therapeutic Potential of Histone Deacetylase Inhibitors

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