Lactate Impairs Vascular Permeability By Inhibiting Hspa12b Expression Via Gpr81-Dependent Signaling In Sepsis 2022 Min et al

Abstract

Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis.

Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay.

Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein–coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice.

Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.

Open access, https://journals.lww.com/shockjourn...CTATE_IMPAIRS_VASCULAR_PERMEABILITY_BY.8.aspx

 

I wonder whether this could allow localized immune activation. For example, maybe it could activate astrocytes directly around a vessel, altering their function and the function of neurons they connect to, without going much further, preventing researchers from seeing any abnormalities.