The role of plasminogen activator inhibitor-2 in pneumococcal meningitis

Abstract

Pneumococcal meningitis is associated with dysregulation of the coagulation cascade. 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 Serpinb2 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. Serpinb2−/− 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.

Identification of potential biomarkers and therapeutic targets related to post-traumatic stress disorder due to traumatic brain injury

“…SERPINB2 participates in multiple cellular functions, including cell survival, cell differentiation, inflammation, immunity, cell adhesion, migration, and extracellular matrix remodeling in multiple disease states via its interactions with intra and extracellular proteins [ 49 – 51 ]. Despite extensive research on SERPINB2, no consensus exists on its pathophysiological functions [ 52 ]. However, a recent study suggests that the downregulation of SERPINB2 may have potential therapeutic value in relieving chronic visceral pain syndromes, such as chronic pelvic pain syndrome within the urological system [ 53 ].…”