Critical Role of IL-1 Receptor-Associated Kinase-M in Regulating Chemokine-Dependent Deleterious Inflammation in Murine Influenza Pneumonia

Abstract

Influenza virus is a common cause of respiratory infection and morbidity, which is often due to deleterious host immune responses directed against the pathogen. We investigated the role of IL-1 receptor-associated kinase-M (IRAK-M), an inhibitor of MyD88-dependent TLR signaling, in modulating the innate inflammatory response during influenza pneumonia using a murine model. The intranasal administration of influenza resulted in the upregulation of IRAK-M mRNA and protein levels in the lungs within 2 d after infectious challenge. Pulmonary influenza infection in mice deficient in IRAK-M (IRAK-M−/−) resulted in substantially increased mortality compared with similarly treated wild-type animals. Increased mortality in IRAK-M−/− mice was associated with enhanced early influx of neutrophils, high permeability edema, apoptosis of lung epithelial cells, markedly increased expression of inflammatory cytokines/chemokines, and release of neutrophil-derived enzymes, including myeloperoxidase and neutrophil elastase. Early viral clearance was not different in mutant mice, whereas viral titers in lungs and blood were significantly higher in IRAK-M−/−mice compared with wild-type animals. Increased lethality observed in IRAK-M−/− mice after influenza challenge was abrogated by Ab-mediated blockade of CXCR2. Collectively, our findings indicate that IRAK-M is critical to preventing deleterious neutrophil-dependent lung injury during influenza infection of the respiratory tract.

Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

“…In contrast to what we found here, the extent of lung inflammation in IRAK-M -/-mice was prolonged over the course of 6 d and associated with an impaired antiviral response and increased lethality (38). Hence, in influenza, pneumonia IRAK-M serves to prevent detrimental inflammation thereby facilitating viral clearance.…”

“…This may, also, at least in part, explain the fact that IRAK-M deficiency was associated with enhanced neutrophil recruitment to the lungs during secondary pneumonia following peritonitis (9), whereas it did not influence neutrophil influx during primary airway infection (this study). In the current investigation, IRAK-M deficiency did not enhance the production of either lipocalin 2 or CCL20, both antimicrobial proteins produced by the respiratory epithelium implicated in host defense against respiratory tract infection (24,25 (38).…”

The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling

“…However IRAK-M -/-mice showed an increased inflammatory response (but not increased susceptibility) to the bacterium Salmonella typhimurium (68). IRAK-M -/-mice were shown to have reduced survival upon influenza infection in vivo (69). Furthermore macrophages derived from IRAK-M knockout mice displayed enhanced activation of IL-1/TLR signalling, thus suggesting a negative role for this family member (68, 69) (see Table 1 …”

Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

“…[31][32][33][34][35][36][37][38][39] IRAK-M-mediated deactivation of proinflammatory macrophages also limits immunopathology during infections as well as osteoclast-driven osteoporosis. 36,40 We speculated that IRAK-M-mediated deactivation of proinflammatory mononuclear phagocytes is required for the resolution of renal inflammation to allow structural and functional tubular reconstitution as a determinant of longterm outcomes upon AKI. We used IRAK-M-deficient mice and long-term follow-up upon postischemic AKI to address this concept.…”