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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Jing Wang1,2
  • Qi Sun1,2
  • Lijuan Li1,2
  • Junmei Xu1,2
  • Lin Yang1,2
  1. 1Department of Anesthesiology, The Second Xiangya Hospital, Central South University
  2. 2Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{wang2026macrophage,
  title = {{Macrophage BMPRIB mediates p38-dependent inflammatory reprogramming and chemotaxis during ventilator-induced lung injury}},
  author = {Jing Wang and Qi Sun and Lijuan Li and Junmei Xu and Lin Yang},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1947415},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947415/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Macrophage BMPRIB mediates p38-dependent inflammatory reprogramming and chemotaxis during ventilator-induced lung injury
AU  - Jing Wang
AU  - Qi Sun
AU  - Lijuan Li
AU  - Junmei Xu
AU  - Lin Yang
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1947415
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1947415/full
AB  - 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.
SN  - 1664-3224
ER  -