Research ArticleCRITICAL CARE

PCSK9 is a critical regulator of the innate immune response and septic shock outcome

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Science Translational Medicine  15 Oct 2014:
Vol. 6, Issue 258, pp. 258ra143
DOI: 10.1126/scitranslmed.3008782

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An Enemy of Translation

Despite nearly 100 clinical trials, potential drugs against murine-derived therapeutic targets for sepsis—a deadly condition caused by overactivation of the innate immune response to microbial infection—have been immune to translation. But humans and microbes have long coexisted fairly symbiotically and have come to share certain biological pathways. Now, Walley et al. show that both host- and pathogen-derived lipids use clearance mechanisms that highlight a well-known protein—proprotein convertase subtilisin/kesin type 9 (PCSK9)—as a possible therapeutic target for selected sepsis patients. The authors show that, compared to wild-type mice, Pcsk9 knockout mice displayed a dampening of various pathophysiological responses to a lipopolysaccharide (LPS) in the cell wall of Gram-negative bacteria. Also, PCSK9 protein inhibited LPS uptake by human liver cells, a crucial step in systemic LPS clearance. Pharmacological inhibition of PCSK9 enhanced survival of mice with polymicrobial peritonitis, a sepsis model. Last, PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients. Drugs that reduce serum cholesterol by inhibiting PCSK9 are being studied in clinical trials as treatments for cardiovascular disease. Then, new work suggests that PCSK9-targeted drugs should be tested in clinical trials with sepsis patients who carry the PCSK9 gain-of-function variant.

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