Alveolar macrophage-derived TGF-β promotes acute lung injury recovery by regulating inflammatory monocyte-derived macrophages

Acute lung injury (ALI) is a rapidly progressive condition with a high mortality rate and limited treatment options. Alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs) are two types of macrophages with distinct characteristics and functions that play pivotal roles in ALI development and repair. However, it remains unclear how these two cell groups coordinate to maintain immune homeostasis.

This study aims to elucidate the underlying causes of immune imbalance during lung injury from the perspective of AMs and MDMs, as well as to clarify how these two cell types collaboratively maintain pulmonary immune homeostasis through their interactions.

ALI mouse model was established. Following AM depletion, lung injury dynamics and MDM phenotypic/numerical changes were analyzed. Regulatory mechanisms of AMs on MDMs were investigated using conditional knockout mice, in vitro co-culture systems, and high-throughput sequencing.

AM deficiency delayed lung injury repair and was associated with significantly increased proliferative capacity and number of inflammatory MDMs. Experiments demonstrated that AMs secrete TGF-β, which promotes their own proliferation while simultaneously inhibiting the proliferation and inflammatory activity of MDMs. Mechanistically, AM-derived TGF-β regulates MDMs by activating the Wnt signaling pathway. Supplementation with TGF-β alleviated both the delayed injury repair caused by AM deficiency and the severity of early-stage lung injury.

AMs critically regulate the inflammatory and proliferative activities of MDMs through TGF-β secretion, which acts via the Wnt signaling pathway. This AM-MDM regulatory axis is essential for timely lung repair and represents a potential therapeutic target for acute lung injury.