Myeloid-specific Becn1 deficiency elicits spontaneous pulmonary injury and exacerbates acute lung injury

Acute lung injury (ALI) and its severe phenotype, acute respiratory distress syndrome (ARDS), represent devastating and highly lethal respiratory disorders. Hallmarked by unrestrained pulmonary inflammation predominantly driven by myeloid cells, these conditions ultimately culminate in profound disruption of the alveolar-capillary barrier. The reciprocal crosstalk between autophagy and inflammation and its molecular underpinnings in ALI pathogenesis remain incompletely defined.

The role of myeloid Becn1 in maintaining pulmonary homeostasis and modulating susceptibility to lipopolysaccharide (LPS)-induced ALI was defined, and the potential link between intestinal barrier integrity, gut microbiota, and ALI severity was further interrogated. The expression of BECN1 in bronchoalveolar lavage fluid (BALF) cells from patients with ARDS and in lung tissues of mice with LPS-induced ALI was detected by western blot and immunofluorescence respectively. Myeloid cell-specific Becn1 conditional knockout (cKO) mice were generated. Parallel analyses were performed in both steady-state and LPS-challenged mice, including quantitative lung histopathological analysis, inflammatory cytokine profiling of BALF, bulk RNA sequencing of lung tissue, histological assessment of intestinal architecture and intestinal tight junction integrity, and 16S rRNA gene sequencing of fecal microbiota.

Myeloid Becn1 deficiency alone was sufficient to disrupt pulmonary homeostasis, leading to spontaneous lung injury characterized by increased alveolar-capillary permeability, inflammatory cell infiltration, and aberrant activation of immune-inflammatory pathways. When challenged with LPS, these pre-existing inflammatory priming effects translated to exacerbated pulmonary pathology and exaggerated cytokine storm. Beyond the lung, Becn1 cKO mice developed spontaneous intestinal barrier dysfunction and gut microbiota dysbiosis at steady state, including blunted intestinal villi, reduced goblet cells, impaired tight junction integrity, increased mast cell infiltration, and a characteristic microbial shift with depleted Actinobacteria and expanded Alistipes. All these intestinal and microbial perturbations were likely further amplified by LPS challenge, consistent with a potential association between intestinal-microbial dysregulation and exacerbated pulmonary injury.

Myeloid Becn1 governs pulmonary-intestinal immune homeostasis, and its deficiency drives spontaneous lung injury, hyperinflammation, impaired gut-lung crosstalk, and exacerbated acute lung injury, establishing myeloid Becn1 as a critical determinant of acute lung injury severity.