Community-acquired respiratory distress syndrome (CARDS) toxin is a key driver of Mycoplasma pneumoniae –mediated disease, yet its pathogenic mechanismsremain incompletely understood. Here, we established female C57BL/6J murine pneumonia models by intratracheal injection of CARDS toxin (700 pmol per mouse). In wild-type mice ( n = 3 per group), single-cell and bulk RNA sequencing were performed to characterize functional alterations of lung macrophages. Pulmonary inflammation was evaluated by immunostaining and PCR analyses in wild-type ( n = 3), Lyz2-Mmp12 −/− ( n = 4), and Mmp12 -CreERT2× Rosa26 -iDTR mice ( n = 5). To interrogate downstream signaling, interleukin-17A (IL-17A) signaling was blocked using a neutralizing antibody. Clinical relevance was assessed by ELISA measurement of bronchoalveolar lavage fluid (BALF) proteins from disease control (DC, n = 20) and M . pneumoniae pneumonia (MPP, n = 52) patients. We demonstrate that CARDS toxin exposure markedly increases the abundance of Mmp12 high macrophages in the murine lung, accompanied by overactivation of pro-inflammatory cytokine signaling. Macrophage-specific Mmp12 knockout attenuated CARDS toxin-induced pulmonary inflammation. Mechanistically, MMP12 promoted T helper 17 cells activation and subsequent IL-17A secretion via SPP1 and FN1, thereby exacerbating pulmonary inflammation. Notably, IL-17A blockade significantly mitigated these responses. Furthermore, MMP12 and IL-17A levels were elevated in the BALF of MPP patients. Collectively, these findings define a pro-inflammatory MMP12–IL-17A axis mediating CARDS toxin-driven pulmonary pathology, highlighting promising therapeutic targets for managing M. pneumoniae –associated respiratory disease. • Community-acquired respiratory distress syndrome (CARDS) toxin increases the abundance of Mmp12 high macrophages in the murine lung. • Mmp12 high macrophages promote Th17 cells activation and subsequent interleukin-17A (IL-17A) secretion via SPP1/FN1. • Blocking IL-17A signaling alleviated alveolar damage and chronic inflammation. • MMP12 and IL-17A proteins are upregulated in the BALF of patients with Mycoplasma pneumoniae pneumonia (MPP).
Xu et al. (Sun,) studied this question.