Research ArticleSepsis

Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis

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Science Translational Medicine  06 Feb 2019:
Vol. 11, Issue 478, eaau5266
DOI: 10.1126/scitranslmed.aau5266

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Sigma-1 receptor subdues systemic inflammation

Systemic inflammation can be lethal, as in the case of septic shock. Rosen et al. hypothesized that the endoplasmic reticulum, now understood to affect inflammation, could be an untapped therapeutic target. They found that mice lacking the endoplasmic reticulum sigma-1 receptor had exacerbated responses to LPS or fecal slurry. The antidepressant fluvoxamine can bind sigma-1 and acts as an agonist. Therapeutic treatment of mice in the two inflammatory models revealed that fluvoxamine lowered inflammatory cytokine production and improved survival. Their results suggest that repurposing fluvoxamine to enhance sigma-1 activity may be beneficial for treating sepsis.

Abstract

Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.

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