Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Abstract

Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M -/-animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M -/-animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

Late mortality after sepsis: propensity matched cohort study

“…Mice that recover from experimental sepsis have accelerated development of atherosclerosis,35 they die with subsequent bacterial or fungal challenge,36 37 38 and they show increased tumor growth 39. High rates of infection, cancer, and deaths related to cardiovascular disease have also been seen in studies of humans who survive sepsis 40.…”

Cecal ligation and puncture induced sepsis impairs host defense against Enterococcus faecium peritonitis

“…Several studies have documented a reduced capacity to release cytokines after CLP and a subsequent challenge with bacterial antigens [23,30,31]. This sepsis-induced immune hyporesponsiveness was shown to impair host defense mechanisms in the lungs against Pseudomonas aeruginosa and Streptococcus pneumoniae [13][14][15]. We here used the CLP model of sepsis to study the course of VRE peritonitis in a host with severe co-morbid disease.…”

“…Cecal ligation and puncture (CLP) is considered a clinically relevant model to study the septic response [12]. Many studies that investigated the sepsis-induced state of immunoparalysis used the model of CLP, especially to examine host defense against secondary pneumonia [13][14][15]. VRE is often cultured from abdominal infections, frequently resulting in subsequent dissemination to blood and distant organs [16,17].…”

Immune cells and oxidative stress in the endotoxin tolerance mouse model

“…The inflammatory response evoked in order to eliminate bacteria is mediated by cytokines that govern the release of enzymes (e.g., metalloproteinases), as well as by those that regulate phagocytosis, oxidative stress, and nitrosative stress (18,19). Proper immune function relies on anti-inflammatory cytokines to appropriately target physiological responses to bacteria.…”

“…Differences in the qualitative and quantitative immune response to microbial stimulation might be critical for the understanding of the pathophysiology of sepsis (5,18). Although T-cell dysfunction is known to occur in sepsis, the increased release of cytokines has received far more attention than have changes in T-cell populations (28).…”