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.