• Wenling Jian, Lili Gu, Brittney Williams, Yan Feng, Wei Chao, and Lin Zou.
• From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (W.J., Y.F., W.C., L.Z.) Translational Research Program, Department of Anesthesiology and Center for Shock Trauma Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland (L.G., B.W., Y.F., W.C., L.Z.) Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China (W.J.).
• Anesthesiology. 2019 Jul 1; 131 (1): 105-118.

What We Already Know About This TopicToll-like receptor 7 responds to elevated single-stranded RNA by increasing cytokine production. Sepsis is characterized by elevated plasma levels of tissue damage (and pathogen)-associated molecular patterns, including RNA.What This Article Tells Us That Is NewUsing murine models of bacterial sepsis, knockout of the Toll-like receptor 7 resulted in lower mortality and cytokine levels and less end-organ injury. Therefore, Toll-like receptor 7, which mediates innate immune response, contributes to harm in experimental sepsis.BackgroundSepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis.MethodsSepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function.ResultsThe 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection.ConclusionsToll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

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