SARM1mediates TLR9-induced vascular hyperpermeability following hemorrhagic shock

Research Article

Received March 14, 2018; Accepted July 29, 2018; Published August 30, 2018
http://dx.doi.org/10.18081/2333-5106/015-10/644-657

Morrison R. Doelle ¹, Benjamin M. Predmore, Adrienne A. Kiss, Henri A. Leuvenink, Robert Clements

Author Affiliations

a Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

Abstract

After hemorrhagic shock, vascular endothelial cell (EC) injury is the primary cause of microcirculatory disturbance. SARM1 plays an important role in the process of microcirculatory injury induced by ischemia-reperfusion. After the TLR9 agonist was treated, wild type mice produced a significantly increased serum level of NE, Ang II, and ET1. However, there was no significant increase in NE, Ang II, and ET1 levels in the SARM1-/- mice. The TLR9-induced serum levels of NE, Ang II, and ET1 from wild type mice were markedly increased after hemorrhagic shock, which were significantly decreased in SARM1-/- mice. The vascular permeability in the peritoneum of sleeper was significantly increased in wild type mice after TLR9 stimulation compared to saline control, which was not observed in SARM1-/- mice. Moreover, SARM1 inhibition could improve the ultrastructure of vascular endothelial cells treated with TLR9 agonist. Our research suggested that the SARM1 inhibitor may have therapeutic potential for sepsis combined with shock by targeting EC-derived TLR9-induced peripheral microvascular hyperpermeability. We found that inhibiting SARM1 in mice could reduce TLR9-induced microvascular leakage and vascular endothelial cell dysfunction, including oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis. Our data demonstrate that inhibiting SARM1 inhibits TLR9-induced microvascular leakage regardless of TLR9 activation in both bone marrow-derived and non-bone marrow-derived blood cells. This study has important clinical implications for a treatment strategy that SARM1 inhibition could be beneficial for septic patients with hemorrhagic shock or trauma by targeting Toll-like receptor 9 (TLR9) in vascular endothelial cells (ECs).

Keywords: Hemorrhagic shock; Inflammatory response; SARM1; TLR9

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