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Here, we collected sheep bronchoalveolar lavage fluid (BALF) 28\u00a0days after infection with\n                    <jats:italic>Mycoplasma ovipneumoniae<\/jats:italic>\n                    (MO). RNA-seq analysis revealed a significant increase in peptidyl arginine deiminase 2 (PADI2) expression in the MO group, and upregulated genes were significantly enriched in the \u201cFoxO signalling pathway\u201d and \u201cAMPK signalling pathway\u201d. Immunohistofluorescence (IHF) staining revealed a significant increase in the number of macrophages, which were widely distributed in the alveolar cavity, in the MO infection group, and PADI2 was also positively expressed in the macrophages. In bone marrow-derived macrophages (BMDMs) isolated in vitro, inhibiting the expression of PADI2 induced infected macrophages to polarize towards alternatively activated (AAM, M2) macrophages. Moreover, the expression levels of the anti-inflammatory gene IL10 and tissue repair-related genes such as vascular endothelial growth factor alpha (VEGFA), transforming growth factor-\u03b2 (TGF-\u03b2), and hepatocyte growth factor (HGF) significantly increased. In an in vitro coculture system, inhibition of PADI2 expression in BMDMs reduced apoptotic and intracellular reactive oxygen species (ROS) levels in lung fibroblasts. Interestingly, correlation analysis between the tracheal MO load and PADI2 expression in the bronchoalveolar lavage fluid of naturally infected MO sheep revealed that the higher the MO load was, the greater the PADI2 expression. A dual luciferase reporter assay confirmed that this process may be regulated by the transcription factor SP3. These results contribute to the understanding of the polarization state of macrophages after mycoplasma infection and to the preliminary exploration of PADI2 as an effective target to enhance host defence against MO infection. Targeting PADI2 to promote the polarization of M2 macrophages provides a promising approach for treating MO infection or preparing anti-Mycoplasma pneumonia gene-edited sheep.\n                  <\/jats:p>","DOI":"10.1186\/s13567-025-01632-7","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T13:13:07Z","timestamp":1761570787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PADI2 exacerbates Mycoplasma ovipneumoniae-induced lung injury in sheep by suppressing M2 macrophage polarization"],"prefix":"10.1186","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5061-5041","authenticated-orcid":false,"given":"Chenbo","family":"Yan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianning","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maojun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"1632_CR1","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.01328-24","volume":"63","author":"LK Weyand","year":"2025","unstructured":"Weyand LK, Felts BL, Cassirer EF, Jenks JA, Walsh DP, Besser TE (2025) Fatal interactions: pneumonia in bighorn lambs following experimental exposure to carriers of Mycoplasma ovipneumoniae. 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