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Neutrophils are a prominent feature in PJI, with neutrophil extracellular traps (NETs) known to be present; little is known, however, about the physiology of PJI-associated NETs. Here, the proteomes of PJI and non-infectious arthroplasty failure (NIAF), analyzed using liquid chromatography tandem mass-spectrometry (LC-MS\/MS) and proximity extension assay (PEA)-based profiling of fluids derived from sonication of arthroplasty components removed from patients who had undergone revision arthroplasty, were compared, with a focus on NET formation. In addition,\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      effects of synovial fluid components on\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus-<\/jats:italic>\n                      induced NET formation were characterized. LC-MS\/MS (PJI\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 85, NIAF\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 26) and PEA (PJI\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 95, NIAF\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 39) showed NET formation and neutrophil degranulation to be associated with PJI, with the complement cascade and platelet activation pathways identified as potential contributors.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      studies showed delayed NET formation in artificial synovial fluid compared to standard cell culture media conventionally used to evaluate NETs. Together, these results demonstrate the presence of NETs in PJI, identify potential pathways involved in PJI-associated NETosis, and point to an influence of synovial components on NET formation during PJI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Periprosthetic joint infection (PJI) is a major complication of joint replacement, placing a significant burden on patients and the healthcare system. Our research reveals that neutrophils and their antimicrobial \u201ctraps\u201d are dominant features of the immune response at the infection joint site. Importantly, we found that the unique environment of the joint delays the formation of these traps, potentially contributing to the pathogenesis of PJI. By establishing a new experimental platform tailored for the infected joint, this work provides a foundational platform for probing these mechanisms and supports the development of improved diagnostic and therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00665-26","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:02:22Z","timestamp":1791896542000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Metaproteomic analysis of human sonicate fluid highlights neutrophil extracellular trap formation associated with periprosthetic joint infection"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1097-6723","authenticated-orcid":true,"given":"Elijah","family":"Garcia","sequence":"first","affiliation":[{"name":"Graduate School of Biomedical Sciences, Mayo Clinic","place":["Rochester, USA"]},{"name":"Alix School of 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