Newly Published
Critical Care Medicine  |   April 2019
Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis
Author Notes
  • 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.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • A part of the work presented in this article has been presented at the 2016 Anesthesiology Annual Meeting, October 22–26, in Chicago, Illinois.
    A part of the work presented in this article has been presented at the 2016 Anesthesiology Annual Meeting, October 22–26, in Chicago, Illinois.×
  • Submitted for publication August 18, 2018. Accepted for publication February 28, 2019.
    Submitted for publication August 18, 2018. Accepted for publication February 28, 2019.×
  • Correspondence: Address correspondence to Dr. Zou: Department of Anesthesiology and Shock Trauma Anesthesiology Research Center, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall 598, Baltimore, Maryland 21201. lzou@som.umaryland.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Gastrointestinal and Hepatic Systems / Infectious Disease
Critical Care Medicine   |   April 2019
Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis
Anesthesiology Newly Published on April 25, 2019. doi:10.1097/ALN.0000000000002706
Anesthesiology Newly Published on April 25, 2019. doi:10.1097/ALN.0000000000002706
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Toll-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 New:

  • Using 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.

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.