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One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so\u2010called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H<jats:sub>2<\/jats:sub>S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine \u03b2\u2010synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H<jats:sub>2<\/jats:sub>S.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low\u2010dose of lipopolysaccharide (LPS; 100\u00a0\u00b5g\u00a0kg<jats:sup>\u22121<\/jats:sup>) daily for four consecutive days. Hypothalamic CBS expression and H<jats:sub>2<\/jats:sub>S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H<jats:sub>2<\/jats:sub>S synthesis (AOA, 100\u00a0pmol\u00a01\u00a0\u00b5L<jats:sup>\u22121<\/jats:sup> icv) or its vehicle in the last day.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Antero\u2010ventral preoptic area of the hypothalamus (AVPO) H<jats:sub>2<\/jats:sub>S production rate and CBS expression were increased in endotoxin\u2010tolerant rats. Additionally, hypothalamic H<jats:sub>2<\/jats:sub>S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE<jats:sub>2<\/jats:sub> levels without altering the absent plasma cytokines surges.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H<jats:sub>2<\/jats:sub>S production modulates most of these mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13373","type":"journal-article","created":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T18:23:36Z","timestamp":1567621416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down\u2010modulating PGE<sub>2<\/sub> production"],"prefix":"10.1111","volume":"228","author":[{"given":"Bruna M.","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Physiology Medical School of Ribeir\u00e3o Preto University of S\u00e3o Paulo Ribeir\u00e3o Preto Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helo\u00edsa D. 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