{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:08:38Z","timestamp":1792796918434,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis, a critical systemic inflammatory response syndrome elicited by pathogenic microorganisms, poses a significant challenge in clinical practice due to its rapid progression and potential for multi-organ failure. This review delineates the intricate roles of Toll-like receptors (TLRs), essential components of the innate immune system, in mediating host responses during sepsis. TLRs recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby initiating signaling cascades that lead to the synthesis of pro-inflammatory cytokines and chemokines. However, the dysregulation of TLR signaling can precipitate a hyper-inflammatory state known as a \u201ccytokine storm,\u201d characterized by excessive tissue damage and complications such as Acute Respiratory Distress Syndrome (ARDS) and acute kidney injury (AKI). Several therapeutic strategies targeting TLR pathways are under exploration to mitigate the adverse effects of sepsis. Despite advancements, significant gaps remain, including the need for robust clinical validation and understanding of TLR expression variability among individuals. Future research should focus on elucidating the precise molecular mechanisms governing TLR-mediated responses and developing human-specific therapeutic interventions. This review aims to consolidate current knowledge on TLRs in sepsis, highlighting their dual roles as both defenders against infection and contributors to pathological conditions, thereby informing future therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1591011","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:43:46Z","timestamp":1746171826000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Comprehending toll-like receptors: pivotal element in the pathogenesis of sepsis and its complications"],"prefix":"10.3389","volume":"16","author":[{"given":"Wei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengtian","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongli","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.7560","article-title":"Fluid therapy for critically ill adults with sepsis: A review","volume":"329","author":"Zampieri","year":"2023","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40779-022-00422-y","article-title":"Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options","volume":"9","author":"Liu","year":"2022","journal-title":"Military Med Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.ccc.2021.11.013","article-title":"Subtypes and mimics of sepsis","volume":"38","author":"Kellum","year":"2022","journal-title":"Crit Care Clin"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00003.2023","article-title":"Sepsis: network pathophysiology and implications for early diagnosis","volume":"324","author":"Arora","year":"2023","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00760-x","article-title":"Mitochondrial control of inflammation","volume":"23","author":"Marchi","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14578","article-title":"Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation","volume":"17","author":"Iba","year":"2019","journal-title":"J Thromb haemostasis: JTH"},{"key":"B8","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/s41392-021-00816-9","article-title":"Signaling pathways and intervention therapies in sepsis","volume":"6","author":"Zhang","year":"2021","journal-title":"Signal transduction targeted Ther"},{"key":"B9","doi-asserted-by":"publisher","first-page":"104318","DOI":"10.1016\/j.ebiom.2022.104318","article-title":"Current sepsis therapeutics","volume":"86","author":"Vincent","year":"2022","journal-title":"EBioMedicine"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpa.2022.03.003","article-title":"Maternal sepsis","volume":"36","author":"Filetici","year":"2022","journal-title":"Best Pract Res Clin Anaesthesiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.20452\/pamw.16290","article-title":"Surviving Sepsis Campaign Guidelines 2021: highlights for the practicing clinician","volume":"132","author":"Oczkowski","year":"2022","journal-title":"Pol Arch Intern Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.coi.2016.10.003","article-title":"Nucleic acid-sensing TLRs: trafficking and regulation","volume":"44","author":"Majer","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"116671","DOI":"10.1016\/j.lfs.2019.116671","article-title":"TLRs in pulmonary diseases","volume":"233","author":"Arora","year":"2019","journal-title":"Life Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098065","article-title":"TLRs: innate immune sentries against SARS-coV-2 infection","volume":"24","author":"Mantovani","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"13397","DOI":"10.3390\/ijms222413397","article-title":"Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) in innate immunity. 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