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However, the mechanisms driving mitochondria-induced NETosis and whether this response can be selectively modulated without impairing antibacterial defense remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the mechanisms of mitochondria-induced NET formation using in vitro, in vivo models and ex vivo, using trauma patient plasma. Neutrophils were exposed to intact mitochondria or mitochondrial components, and the roles of Toll-like receptor 9 (TLR9), formyl peptide receptor 1 (FPR1), PAD4, NOX2, p38\u03b1, and STAT6 were assessed. Effect of the synthetic FPR1 agonist FPRA14 on NET formation and antibacterial neutrophil functions was tested in double hit in vivo model of peritoneal mitochondria injection followed by\n                      <jats:italic>S. aureus<\/jats:italic>\n                      pneumonia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Intact mitochondria induced NET formation through coordinated activation of both TLR9 and FPR1, with dependence on PAD4, NOX2, and p38\u03b1 signaling. Mitochondrial protein integrity was important for this response, likely by protecting mtDNA from degradation and enabling TLR9 activation. While insufficient to drive NETosis alone, FPR1 activation showed a concentration- and time-dependent modulatory effect: low-level activation promoted NETosis, whereas stronger or pre-exposure\u2013induced signaling suppressed it through receptor desensitization. FPR1 agonist FPRA14 reduced mitochondria-driven NET formation in vitro and in a double hit murine model while preserving neutrophil antibacterial functions, including NET formation, phagocytosis, ROS generation, bacterial killing, and infection control. p38\u03b1 acted as a positive regulator, whereas STAT6 functioned as a negative regulator of NET formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify FPR1 as a key regulator of pathological mitochondria-driven NETosis and suggest that selective FPR1 receptor desensitization may suppress excessive sterile inflammation without compromising host defense. This work extends current understanding of mtDAMP signaling in neutrophils and supports prophylactic FPR1 agonism as a potential strategy for limiting inflammatory tissue damage after trauma or surgery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Mitochondria-induced NETosis depends on TLR9\/FPR1 signaling and can be reduced by FPR1 agonism without compromising antibacterial immunity. FPRA14 may represent a strategy to limit harmful sterile inflammation after trauma or surgery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-026-01522-4","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T07:26:14Z","timestamp":1781335574000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Formyl peptide receptor 1 agonism selectively suppresses mitochondria-driven neutrophil extracellular trap formation while preserving antibacterial immunity"],"prefix":"10.1186","volume":"32","author":[{"given":"Emil","family":"Be\u010dka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Let\u00edcia","family":"Hudecov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik","family":"Bertovi\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol\u00edna","family":"B\u00edla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u013dudmila","family":"Podrack\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Celec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Pastorek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"1522_CR1","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3389\/fvets.2020.00260","volume":"7","author":"P Alarc\u00f3n","year":"2020","unstructured":"Alarc\u00f3n P, Manosalva C, Quiroga J, Belmar I, \u00c1lvarez K, D\u00edaz G, et al. 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