Cutting Edge: Myeloid Differentiation Factor 88 Deficiency Improves Resistance Against Sepsis Caused by Polymicrobial Infection

Abstract

Toll-like receptors (TLRs) are important for the activation of innate immune cells upon encounter of microbial pathogens. The present study investigated the potential roles of TLR2, TLR4, and the signaling protein myeloid differentiation factor 88 (MyD88) in polymicrobial septic peritonitis. Whereas both TLR2 and TLR4 were dispensable for host defense against septic peritonitis, MyD88-deficient mice were protected in this infection model. Recruitment of neutrophils to the septic focus and bacterial clearance were normal in MyD88-deficient mice. In contrast, the systemic inflammatory response was strongly attenuated in the absence of MyD88. Surprisingly, MyD88 deficiency did not alter cytokine and chemokine production in spleen, but markedly reduced the inflammatory response in liver and lung. Production of monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1α was entirely independent of MyD88. These results imply a central role of MyD88 for the systemic immune pathology of polymicrobial sepsis and show that cytokine production in spleen and induction of certain chemokines are MyD88 independent.

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

“…Whereas CCL2 levels exhibited a partial, but significant, reduction in MyD88-deficient mice as compared to wild-type controls, production of CCL12 was similar in both groups. These results on the regulation of local chemokine production are consistent with our previous analyses, showing MyD88-independent expression of CCL2 in peripheral organs such as liver, lung, and spleen [11], which represent secondary sites of infection during septic peritonitis.…”

“…2). Consistent with our previous data [11], the results in Fig. 2 also confirm that cell recruitment to the infected peritoneal cavity was independent of MyD88.…”

“…Previous work showed that genetic deficiency of MyD88 protected mice from the lethal effects of polymicrobial septic peritonitis and that the hyperinflammatory response to sepsis was strongly attenuated in the absence of MyD88 [11]. In contrast, recruitment of neutrophils to the infected peritoneal cavity and bacterial clearance were not altered in MyD88-deficient mice, suggesting that the MyD88-dependent signaling pathway contributes to the immune pathology of sepsis but is dispensable for anti-bacterial defense.…”

“…Elevated levels of CCL2 have been detected in plasma of sepsis patients, after administration of LPS to human volunteers, and in animal models of endotoxemia or septic peritonitis [11,[18][19][20][21][22]. Moreover, neutralization of CCL2 aggravated the lethal effects of LPS administration or cecal ligation and puncture in experimental animals [18,19].…”

The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes

“…Even the LPS recognition complex and signal transduction pathway involves many candidate genes, in which various polymorphisms may alter phenotype. These include candidate polymorphisms in genes for bactericidal/ permeability increasing protein, LBP, 6,33 CD14, 34-36 MD-2, 37 Myeloid Differentiation Factor 88 (MyD88), 38,39 and IL-1 receptor-associated kinase (IRAK). 40,41 As other have stated, the genetic determinants responsible for the host response to injury or infection are largely polygenic or weakly penetrant.…”