@article{Xu2026, 
author = {Yuling Xu and Xun Wang and Ning Yang and Xinyu Yang and Lin Gu and Zhaohui Tong and Nan Song and Jieqiong Li},
title = {MMP12 exacerbates pulmonary inflammation by enhancing IL-17A expression},
year = {2026},
journal = {hLife},
volume = {4},
number = {5},
pages = {309-326},
keywords = {Mycoplasma pneumoniae, community-acquired respiratory distress syndrome (CARDS) toxin, matrix metalloproteinase 12, interleukin-17A (IL-17A), pulmonary inflammation},
url = {https://www.sciopen.com/article/10.1016/j.hlife.2026.03.002},
doi = {10.1016/j.hlife.2026.03.002},
abstract = {Community-acquired respiratory distress syndrome (CARDS) toxin is a key driver of Mycoplasma pneumoniae–mediated disease, yet its pathogenic mechanisms remain 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 using proteomic analysis and ELISA measurements of bronchoalveolar lavage fluid (BALF) proteins from disease control (n = 26) and M. pneumoniae pneumonia (MPP, n = 58) patients. We demonstrate that CARDS toxin exposure markedly increases the abundance of Mmp12high 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.}
}