Synergistic regulation of microglia differentiation by CD93 and integrin β1 in the rat pneumococcal meningitis model.

Streptococcus pneumoniae is the main bacterial pathogen of meningitis worldwide, which has a high mortality rate and survivors are prone to central nervous system (CNS) sequelae. In this regard, microglia activation has been associated with injury to the CNS. The aim of this study was to investigate the relationship between CD93, integrin β1, and microglia activation. In the rat pneumococcal meningitis model, we found significant increases of CD93 and integrin β1 expression and differentiation of M1 phenotype microglia. Furthermore, we showed in vitro siRNA-mediated downregulation of CD93 and integrin β1 expression after infecting highly aggressive proliferating immortalized (HAPI) microglia cells with S. pneumoniae. We observed differentiation of S. pneumonia-infected HAPI microglia cells to the M1 phenotype and significant release of soluble CD93 (sCD93) and integrin β1 expression. Complement C1q and metalloproteinases promoted sCD93 release. We also showed that downregulation of CD93 significantly reduced differentiation to M1 microglia and increased differentiation to M2 microglia. However, addition of recombinant CD93 may regulate microglia differentiation to the M1 phenotype. Furthermore, the downregulation of integrin β1 resulted in downregulation of the CD93 protein. In conclusion, interaction between integrin β1 and CD93 promotes differentiation of microglia to the M1 phenotype, increases the release of pro-inflammatory factors, and leads to nervous system injury in pneumococcal meningitis.