Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis 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. Methods Sepsis 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. Results The 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. Conclusions Toll-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.

Toll‐like receptors 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis

“…To rule out the possibility that TLR7 deficiency may alter the gut microbiomes, leading to reduced bacterial virulence and an improved coagulation profile as compared with WT mice, we tested the virulence of the gut microbiomes in a fecal slurry model. We found that the fecal slurry model generated similar degree of hypothermia (28.0°C ± 2.0°C vs 28.7°C ± 1.7°C) and MCF reduction (48.3 ± 19.18 mm vs 52.4 ± 13.28 mm), and comparable levels of plasma cytokines, as the CLP model in WT mice. Importantly, we found no difference in the degrees of hypothermia and coagulation dysfunction between WT mice receiving WT fecal slurry and those receiving TLR7 −/− fecal slurry.…”

Extracellular miR-146a-5p Induces Cardiac Innate Immune Response and Cardiomyocyte Dysfunction

“…Neonatal rats (Sprague Dawley) were purchased from Charles River (Wilmington, MA). Mice were housed and fed as specified in a previous publication ( 17 ). WT mice were housed for at least 1 wk prior to being used in experiments.…”

Role of extracellular microRNA-146a-5p in host innate immunity and bacterial sepsis

“…Although the definite contribution of the proinflammatory function of miR-146a-5p to sepsis is yet to be determined, these findings clearly suggest that host endogenous miR-146a-5p functions as an innate immune activator and plays a contributory role in driving systemic inflammation and organ injury in sepsis. Supporting this are the recent reports that mice deficient of TLR7, the nucleic acid sensor for single-stranded RNA, are protected from sepsis-induced systemic cytokine storm, coagulopathy, and organ injury ( Jian et al., 2019 ; Williams et al . , 2019 ).…”