NOD1 promotes leukocyte clearance and limits inflammation in female mice during obesity-associated acute lung injury.

Obesity is associated with metabolic inflammation, which includes changes to innate immune responses relevant to acute lung injury. NOD1 is a cytosolic pattern recognition receptor involved in sensing bacterial peptidoglycan and has been linked to metabolic inflammation. However, its role in obesity-associated acute lung injury, especially in females, remains unclear. Here, we investigated the impact of NOD1 deficiency on pulmonary inflammation in female mice subjected to a high-fat diet and lipopolysaccharide-induced acute lung injury. Compared to wild-type controls, obese Nod1(-/-) mice showed reduced leukocyte and neutrophil numbers in the bronchoalveolar lavage (BAL), but increased BAL levels of TNF-α, IL-1β, IL-6, IL-17A, and IL-22, suggesting impaired neutrophil clearance. In the lung tissue, NOD1 deficiency during obesity led to elevated neutrophil accumulation, increased myeloperoxidase activity, reduced CD163(+) macrophages, and enhanced β-galactosidase activity. Gene expression analysis revealed upregulation of chemokines, adhesion molecules, and inflammasome components, alongside downregulation of M2 polarization markers. Additionally, obese Nod1(-/-) mice showed higher NF-κB and ERK1/2 activation and lower p38 phosphorylation. These findings indicate that NOD1 regulates leukocyte dynamics, inflammation, and macrophage function in the obese lung. We identify NOD1 as a key protective modulator of pulmonary immune responses during acute lung injury under metabolic stress.