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Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL‐1 receptor‐related protein (SIGIRR), a negative regulator of IL‐1 receptor and Toll‐like receptor signalling, inhibits lipopolysaccharide (LPS)‐induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS‐challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18−/− mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS‐induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4‐mediated inflammasome activation and thereby potentiated IL‐1β production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI. [ABSTRACT FROM AUTHOR]

Alveolar macrophages exist in the lung airspaces, and their differentiation and function are considerably regulated by the microenvironment. In this study, we examine the important role of resident neutrophil/ IL-23/granulocyte/macrophage colony-stimulating factor ( GM- CSF) axis in the development and preferential phenotype of alveolar macrophages under physiological conditions. Using CD18-deficient ( CD18 −/−) mice, we show a correlation between increased granulopoiesis and enhanced alveolar macrophage development in an IL-23- and GM- CSF-dependent manner. The apoptotic neutrophils could inhibit the secretion of IL-23 from alveolar macrophages, which is important for the production of GM- CSF, and depletion of neutrophils disrupted the regulation of IL-23 and GM- CSF. This study reveals a mechanism for the regulation of the local alveolar macrophage population and function by neutrophil apoptosis in the circulatory system. [ABSTRACT FROM AUTHOR]