Insulin-like growth factor-1/insulin-like growth factor-1 receptor signalling in macrophages facilitates recovery from acute lung injury.

Abstract

BACKGROUND: No effective treatment strategy for acute respiratory distress syndrome (ARDS) has been established. Conflicting reports on the effects of insulin-like growth factor (IGF)-1 stimulation and the inhibition of IGF-1 receptor (IGF-1R) signalling in tissue injury across several organs have led to hesitation in advancing IGF-1-based treatment strategies for tissue damage. OBJECTIVE: We aim to examine whether IGF-1/IGF-1R signalling contributes to recovery from acute lung injury in mouse models and to further explore its potential mechanisms. METHODS: Lipopolysaccharide (LPS) was intratracheally injected into mice to create acute lung injury models. Experiments were conducted to acquire or inhibit IGF-1 signalling through the intratracheal injection of recombinant IGF-1 or JB1, an IGF-1 receptor antagonist during the recovery phase of the models, starting on day 4 after LPS administration. Bone marrow monocyte-derived macrophages (MDMs) cocultured with IGF-1 and/or JB1 were intratracheally injected during the recovery phase. RESULTS: Inflammatory cell counts and lung injury scores were significantly decreased when recombinant IGF-1 was administered in the later phase, while they increased with the administration of JB1. On day 4 after LPS injection, IGF-1 receptor (IGF-1R, also known as CD221) was strongly expressed on macrophages, particularly in CD11cSiglecFalveolar macrophages (AMs). Intratracheal injection of MDMs cocultured with IGF-1 decreased lung neutrophil counts, whereas the addition of JB1 to MDMs cocultured with IGF-1 counteracted the effect of IGF-1. JB1 also reduced efferocytosis capacity of AMs in the later phase. In the phagocytosis assay, LPS decreased the efflux capacity of macrophages, but recombinant IGF-1 improved this capacity regardless of the presence or absence of LPS. CONCLUSION: IGF-1/IGF-1R signalling in macrophage facilitates the recovery from acute lung injuryenhancing efferocytosis. IGF-1 delivery potentially offers a new treatment strategy for ARDS.