{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:07:34Z","timestamp":1789168054256,"version":"build-2803163510"},"reference-count":125,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NOSMUFA Research Development"},{"name":"Natural Sciences and Engineering Research Council of Canada (NSERC)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK\/MAPK, p38\/MAPK, JNK\/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis.<\/jats:p>","DOI":"10.3390\/ijms251910673","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T07:59:59Z","timestamp":1727942399000},"page":"10673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["C5a Induces Inflammatory Signaling and Apoptosis in PC12 Cells through C5aR-Dependent Signaling: A Potential Mechanism for Adrenal Damage in Sepsis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9190-7020","authenticated-orcid":false,"given":"Lucas","family":"Mrozewski","sequence":"first","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujeenthar","family":"Tharmalingam","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Medical Science Division, NOSM University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Michael","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aseem","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Medical Science Division, NOSM University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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