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While many pro-inflammatory cytokines contributing to this cascade reach peak upregulation within 24 h, Interleukin-18 (IL-18) exhibits a delayed upregulation profile, typically peaking 7 days post-injury. This review examines the temporal regulation and cell-specific roles contributing to the rise in IL-18 after SCI. Following primary insult, damage-associated molecular patterns prime and activate the NLRP3 inflammasome, which in turn drives latent IL-18 secretion. Cellularly, microglia function as the primary producers of IL-18 via the TLR4\/p38-MAPK pathway, while astrocytes serve as the primary responders through IL-18R\/p65-NF-\u03ba\u03b2 signaling. The microglia-astrocyte cross-talk propagates reactive gliosis, drives neuropathic pain, facilitates neuronal loss, and potentially contributes to the formation of the astrocytic border. Targeted therapeutic interventions such as upstream inhibition of NLRP3 inflammasome assembly or direct IL-18 neutralization successfully mitigate neuroinflammation. By either inhibiting NLRP3 inflammasome activation or directly neutralizing IL-18, these treatments shift the microglial toward a protective state, restrict histological damage, and significantly improve functional recovery.<\/jats:p>","DOI":"10.3390\/cells15111011","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T08:09:16Z","timestamp":1780301356000},"page":"1011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Interleukin-18 After Spinal Cord Injury: Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9194-1217","authenticated-orcid":false,"given":"Luke J.","family":"Bolstad","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3115-7850","authenticated-orcid":false,"given":"Mia J.","family":"LaRico","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Zanovich","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant R.","family":"Keith","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5062-5952","authenticated-orcid":false,"given":"Amgad S.","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-5752","authenticated-orcid":false,"given":"Daniel J.","family":"Hellenbrand","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, M., Jeong, W., Jang, S., Park, J.H., Bae, Y., and Lee, S.W. 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