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Nearly 5% of the 14\u00a0million craniotomies performed worldwide each year become infected, most often with <jats:italic>Staphylococcus aureus<\/jats:italic> (<jats:italic>S. aureus<\/jats:italic>), which forms a biofilm on the surface of the resected bone segment to establish a chronic infection that is recalcitrant to antibiotics and immune-mediated clearance. Tumor necrosis factor (TNF), a prototypical proinflammatory cytokine, has been implicated in generating protective immunity to various infections. Although TNF is elevated during <jats:italic>S. aureus<\/jats:italic> craniotomy infection, its functional importance in regulating disease pathogenesis has not been explored.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A mouse model of <jats:italic>S. aureus<\/jats:italic> craniotomy infection was used to investigate the functional importance of TNF signaling using TNF, TNFR1, and TNFR2 knockout (KO) mice by quantifying bacterial burden, immune infiltrates, inflammatory mediators, and transcriptional changes by RNA-seq.\u00a0Complementary experiments examined neutrophil extracellular trap formation, leukocyte apoptosis, phagocytosis, and bactericidal activity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>TNF transiently regulated neutrophil and granulocytic myeloid-derived suppressor cell recruitment to the brain, subcutaneous galea, and bone flap as evident by significant reductions in both cell types between days 7 to 14 post-infection coinciding with significant decreases in several chemokines, which recovered to wild type levels by day 28. Despite these defects, bacterial burdens were similar in TNF KO and WT mice. RNA-seq revealed enhanced lymphotoxin-\u03b1 (<jats:italic>Lta<\/jats:italic>) expression in TNF KO granulocytes. Since both TNF and LT\u03b1 signal through TNFR1 and TNFR2, KO mice for each receptor were examined to assess potential redundancy; however, neither strain had any impact on <jats:italic>S. aureus<\/jats:italic> burden. In vitro studies revealed that TNF loss selectively altered macrophage responses to <jats:italic>S. aureus<\/jats:italic> since TNF KO macrophages displayed significant reductions in phagocytosis, apoptosis, IL-6 production, and bactericidal activity in response to live <jats:italic>S. aureus<\/jats:italic>, whereas granulocytes were not affected.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These findings implicate TNF in modulating granulocyte recruitment during acute craniotomy infection via secondary effects on chemokine production and identify macrophages as a key cellular target of TNF action. However, the lack of changes in bacterial burden in TNF KO animals suggests the involvement of additional signals that dictate <jats:italic>S. aureus<\/jats:italic> pathogenesis during craniotomy infection.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-024-03174-9","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T10:12:46Z","timestamp":1721729566000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tumor necrosis factor regulates leukocyte recruitment but not bacterial persistence during Staphylococcus aureus craniotomy infection"],"prefix":"10.1186","volume":"21","author":[{"given":"Zachary","family":"Van Roy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Kielian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"3174_CR1","doi-asserted-by":"publisher","first-page":"625467","DOI":"10.3389\/fimmu.2021.625467","volume":"12","author":"SD de Morais","year":"2021","unstructured":"de Morais SD, Kak G, Menousek JP, Kielian T. 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