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 signaling 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 signaling, 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 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