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Previously, we detected upregulation of cerebral plasminogen activator inhibitor-2 (PAI-2) mRNA expression during pneumococcal meningitis. Diverse functions have been ascribed to PAI-2, but its role remains unclear. We analyzed the function of SERPINB2 (coding for PAI-2) in patients with bacterial meningitis, in a well-established pneumococcal meningitis mouse model, using<jats:italic>Serpinb2<\/jats:italic>knockout mice, and in vitro in wt and PAI-2-deficient bone marrow-derived macrophages (BMDMs). We measured PAI-2 in cerebrospinal fluid of patients, and performed functional, histopathological, protein and mRNA expression analyses in vivo and in vitro. We found a substantial increase of PAI-2 concentration in CSF of patients with pneumococcal meningitis, and up-regulation and increased release of PAI-2 in mice. PAI-2 deficiency was associated with increased mortality in murine pneumococcal meningitis and cerebral hemorrhages.<jats:italic>Serpinb2<\/jats:italic><jats:sup><jats:italic>\u2212\/<\/jats:italic>\u2212<\/jats:sup>mice exhibited increased C5a levels, but decreased IL-10 levels in the brain during pneumococcal infection. Our in vitro experiments confirmed increased expression and release of PAI-2 by wt BMDM and decreased IL-10 liberation by PAI-2-deficient BMDM upon pneumococcal challenge. Our data show that PAI-2 is elevated during in pneumococcal meningitis in humans and mice. PAI-2 deficiency causes an inflammatory imbalance, resulting in increased brain pathology and mortality.<\/jats:p>","DOI":"10.1186\/s40478-022-01461-1","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T09:05:34Z","timestamp":1667034334000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The role of plasminogen activator inhibitor-2 in pneumococcal meningitis"],"prefix":"10.1186","volume":"10","author":[{"given":"Nina C.","family":"Teske","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo-Yeon","family":"Engelen-Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Dyckhoff-Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Walter","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diederik","family":"van de Beek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten K.","family":"Kirschning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Koedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7775-7843","authenticated-orcid":false,"given":"Matthijs C.","family":"Brouwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,29]]},"reference":[{"key":"1461_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.2174\/1871525712666141106095927","volume":"12","author":"R Al-Horani","year":"2014","unstructured":"Al-Horani R (2014) Serpin regulation of fibrinolytic system: implications for therapeutic applications in cardiovascular diseases. 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Written informed consent was obtained from all participating patients, or their legally authorized representatives, and controls. The animal experiments were approved by the animal ethic committee of the government of Upper Bavaria, Germany (AZ 211\u20132531-67\/99 und -47\/08).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"155"}}