Macrophage BMPRIB mediates p38-dependent inflammatory reprogramming and chemotaxis during ventilator-induced lung injury.

Background: Ventilator-induced lung injury (VILI) is a major iatrogenic complication of mechanical ventilation, in which dysregulated inflammation, particularly macrophage-driven response, amplifies pulmonary damage. Although bone morphogenetic protein (BMP) signaling exhibits context-dependent effects in pulmonary disorders, whether specific BMP receptors (BMPRs) regulate macrophage function during VILI remains unknown. Methods: Mice subjected to mechanical ventilation were randomly divided into Control (intubation without ventilation), LVT (low tidal volume), and HVT (high tidal volume) groups. HVT-exposed mice received intratracheal administration of exogenous BMP4 or the BMP type I receptor antagonist LDN193189. Lung injury severity was assessed by ultrasound, macroscopic scoring, wet/dry ratio, and histopathology. Macrophage accumulation, M1/M2 polarization, interstitial-to-alveolar macrophage (IM/AM) ratio, and BMP receptor expression were evaluated. Transcriptomic profiling was performed to identify differentially expressed genes and enriched pathways. In vitro, gain- and loss-of-function experiments (overexpression and knockdown of BMPRIB) were conducted in RAW264.7 macrophages to assess cytokine/chemokine production, migration, and MAPK pathway activation. The p38 inhibitor SB202190 was used to probe downstream signaling. Results: Compared with Control and LVT groups, HVT induced time-dependent macrophage accumulation, skewed M1/M2 polarization, and a progressive elevation of the IM/AM ratio. Strikingly, HVT selectively upregulated BMPRIB in lung macrophages, while downregulating BMPRII and leaving BMPRIA unchanged. Intratracheal BMP4 exacerbated these effects, whereas LDN193189 reversed BMP4-induced macrophage accumulation, M1 polarization, IM/AM elevation, and suppressed activation of ERK, JNK, p38, and p65 signaling. Transcriptomic analysis revealed that BMP4 enriched MAPK and inflammation-related pathways, with LDN193189 co-treatment partially reversing this enrichment. In BMP4-stimulated RAW264.7 macrophages, BMPRIB overexpression enhanced, whereas BMPRIB knockdown attenuated, cytokine/chemokine production and migration. Pharmacological p38 inhibition (SB202190) abrogated BMP4-induced pro-inflammatory effects in macrophages. Conclusions: HVT-induced BMPRIB upregulation in lung macrophages allows BMP4 to activate BMPRIB-dependent p38/NF-κB p65 axis as a key mediator of macrophage-driven inflammation in VILI Targeting the BMPRIB-dependent p38/NF-κB axis may represent a novel therapeutic strategy.