Staphylococcus aureus–induced endothelial permeability and inflammation are mediated by microtubule destabilization

Abstract

Edited by Velia M. FowlerStaphylococcus aureus is a major etiological agent of sepsis and induces endothelial cell (EC) barrier dysfunction and inflammation, two major hallmarks of acute lung injury. However, the molecular mechanisms of bacterial pathogen-induced EC barrier disruption are incompletely understood. Here, we investigated the role of microtubules (MT) in the mechanisms of EC barrier compromise caused by heat-killed S. aureus (HKSA). Using a customized monolayer permeability assay in human pulmonary EC and MT fractionation, we observed that HKSAinduced barrier disruption is accompanied by MT destabilization and increased histone deacetylase-6 (HDAC6) activity resulting from elevated reactive oxygen species (ROS) production. Molecular or pharmacological HDAC6 inhibition rescued barrier function in HKSA-challenged vascular endothelium. The HKSA-induced EC permeability was associated with impaired MT-mediated delivery of cytoplasmic linkerassociated protein 2 (CLASP2) to the cell periphery, limiting its interaction with adherens junction proteins. HKSA-induced EC barrier dysfunction was also associated with increased Rho GTPase activity via activation of MT-bound Rho-specific guanine nucleotide exchange factor-H1 (GEF-H1) and was abolished by HDAC6 down-regulation. HKSA activated the NF-B proinflammatory pathway and increased the expression of intercellular and vascular cell adhesion molecules in EC, an effect that was also HDAC6-dependent and mediated, at least in part, by a GEF-H1/Rho-dependent mechanism. Of note, HDAC6 knockout mice or HDAC6 inhibitor-treated WT mice were partially protected from vascular leakage and inflammation caused by both HKSA or methicillin-resistant S. aureus (MRSA). Our results indicate that S. aureus-induced, ROS-dependent up-regulation of HDAC6 activity destabilizes MT and thereby activates the GEF-H1/Rho pathway, increasing both EC permeability and inflammation.

Pharmacological Inhibition of HDAC6 Attenuates NLRP3 Inflammatory Response and Protects Dopaminergic Neurons in Experimental Models of Parkinson’s Disease

“…NLRP3 plays a vital role in autoimmune diseases, and NLRP3-induced maturation of pro-inflammatory cytokines is implicated in PD pathogenesis (Martinez et al, 2017). Given the role of HDAC6 specific inhibitors in inflammatory conditions (de Zoeten et al, 2011;Di Liddo et al, 2016;Chang et al, 2018;Karki et al, 2019;Ran and Zhou, 2019), we examined whether NLRP3 is a potential molecular target of HDAC6 for the regulation of cellular events in PD. We found that NLRP3 was significantly activated after 6-OHDA injury but could be suppressed by TBA, and TBA alleviated glial cell proliferation.…”

“…DD1 and DD2 contribute to the enzymatic activity of HDAC6 (i.e., deacetylation activity), and ZnF-UBP exerts non-enzymatic effects (i.e., ubiquitin-binding activity) (Du et al, 2010). Accumulating studies have demonstrated that pharmacological inhibition of HDAC6 promotes Treg suppressive activity in models of autoimmunity and inflammation (de Zoeten et al, 2011), and the HDAC6 selective inhibitor MC2780 inhibits host inflammation in silicone implants by reducing thickness of peri-implant fibrous capsule and production of IL-1β (Di Liddo et al, 2016); in addition, inhibition of HDAC6 with ACY1083 protects intestine by attenuating inflammation during hemorrhagic shock (Chang et al, 2018), and pharmacological inhibitors of HDAC6-treated mice are protected from inflammatory responses caused by methicillin-resistant Staphylococcus aureus (Karki et al, 2019). Therefore, these studies indicate that HDAC6 inhibitors, which target deacetylase catalytic domains only (Miyake et al, 2016), exhibit anti-inflammatory properties in various pathologic conditions.…”

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics

“…In addition, caveolae-mediated endocytosis which exists in muscles, among others [100], could have functioned as transcytosis pathway [101,102]. However, in the clinical scenario of implant infection, increased endothelial permeability is present [103,104] and therewith overcoming the first barrier, the transfer from blood vessel into the infected tissue surrounding the implant, should probably occur.…”

“…Although clinically relevant accumulation of MNPSNPs at the implant surface could not be shown in the present study, this concept constitutes a great potential because several factors are different in the scenario of an infected implant in humans. When implantassociated infection occurs, the vascular permeability of surrounding tissue is automatically enhanced [104] and nanoparticles should be able to accumulate in the implant region. Accordingly, the significant difference towards the control implant will arise from MNPSNPs overcoming the distance between blood vessel and implant surface only in case of occurring magnetic field gradient.…”

SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells

“…Although Rho activation and increased endothelial barrier permeability is typically accompanied by increased inflammation in response to pro-inflammatory agonists 55 , this relationship may no longer apply to endothelial cells that have acquired a mesenchymal phenotype such as that induced by SIRT7 depletion. Together, our findings suggest that EndoMT is a central mechanism both for the anti-inflammatory effects and increased vascular permeability induced by SIRT7 depletion in pulmonary endothelium.…”