Unveiling the Mechanisms of Chlamydia-Induced Neutrophilic Airway Inflammation

Chlamydia pneumoniae has been implicated in worsening asthma by inducing neutrophilia in the airways, leading to increased severity of airway diseases. Failure to eliminate C. pneumoniae can trigger a robust inflammatory response, resulting in elevated cytokine levels and airway remodeling. Neutrophilic extracellular dsDNA from neutrophil extracellular traps (NETs) exacerbates airway inflammation and tissue damage, contributing to the pathogenesis of asthma or cystic fibrosis (CF). NETs activate complements like C5a and stimulate cytokine production. To investigate the link between Chlamydia infections, NETosis, and airway inflammation, Balb/c mice were infected with species-specific C. muridarum or C. pneumoniae or left untreated. Proteomic GSEA analysis of lung samples revealed significant alterations in protein expression, with C. pneumoniae upregulating neutrophil elastase (NE), myeloperoxidase (MPO), cathelicidin, and downregulating proteins associated with lytic NETosis, while C. muridarum showed activation of C5aR1, PAD4, and calcium signaling. Our findings suggest that C. pneumoniae predominantly activates the classical complement pathway via C1q and C5aR, while C. muridarum activates the alternative pathway via C3 and properdin. Measurement of dsDNA using the PicoGreen assay showed significantly higher levels in BAL of the infected mice compared to controls. In vitro experiments with Chlamydia-treated neutrophils exhibited elevated dsDNA levels. Our results indicate that Chlamydia species induce NETosis and complement activation through distinct mechanisms, highlighting the potential of using C. pneumoniae to model human airway NETosis. As infection-induced NETosis impacts disease severity, our findings support further research into the development of NETs inhibitors.