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To identify both cardioprotective and regenerative mechanisms, we compared activated genes and related signaling pathways in the neonatal mouse heart after myocardial infarction (MI) and after exposure to pressure overload using a neonatal model of transverse aortic constriction (nTAC) at postnatal day 1 (P1). We identified three immune-related genes\u2014Ccl4, S100a8, and C1qa\u2014of high interest, as they encode secreted factors, are highly expressed in the neonatal mouse heart in both injury types, and their receptors are expressed on neonatal cardiomyocytes (nCM) and cardiac endothelial cells (EC). We investigated their effects on primary mouse EC and nCM in vitro. Our study found that the combination of these secreted factors (Pool3) enhances EC and nCM cell cycle re-entry and reduces the rate of apoptosis. Combined in vivo and in vitro transcriptome analyses revealed that Toll-like receptor 2 (TLR2) activation in nCM induces a shared pro-survival and cell cycle re-entry-associated signaling, including upregulation of Bcl2 and Birc5, respectively. The direct and pivotal role of TLR2 in enhancing nCM cell cycle re-entry and survival was further confirmed using TLR2 knockout (KO) nCM, a TLR2 inhibitor, and a TLR2 agonist (zymosan). Moreover, the importance of TLR2 in mediating the adaptive response to pressure overload in neonatal mice was confirmed in TLR2 KO mice, which failed to adapt to pressure overload and exhibited high mortality together with maladaptive cardiac remodeling as early as 7 days post-surgery. Collectively, these findings demonstrate that TLR2 is essential for mediating nCM cell cycle re-entry, survival, and adaptive\/regenerative response to injury.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>Schematic image of immune-cardiomyocyte crosstalk via TLR2 during cardiac injury in neonatal mice. TLR2 activation in response to secreted immune cytokines such as CCL4, C1QA, and S100A8 during cardiac injury promotes nCM survival and cell cycle re-entry via upregulation of Bcl2 and Birc5, respectively<\/jats:p>","DOI":"10.1186\/s12964-026-03147-w","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:34:56Z","timestamp":1786707296000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TLR2 mediates cell cycle re-entry and survival of neonatal cardiomyocytes in response to injury"],"prefix":"10.1186","volume":"24","author":[{"given":"Julia","family":"Nicke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Goldspink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Menn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd K.","family":"Fleischmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8410-7865","authenticated-orcid":false,"given":"Mona","family":"Malek Mohammadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"3147_CR1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1164680","volume":"324","author":"O Bergmann","year":"2009","unstructured":"Bergmann O, et al. 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