Pharmacologic depletion of border-associated macrophages worsens disease in a mouse model of meningitis.

Pneumococcal infection of the leptomeninges triggers a strong inflammatory response, contributing to tissue damage and adverse outcome in meningitis. While border-associated macrophages (BAM) are thought to initiate immune responses against pathogens, their exact role in pneumococcal meningitis (PM) - especially at later stages - remains unclear. This study examined the impact of BAM depletion on disease progression. Mice received intracisternal injections of clodronate liposomes (CL) to deplete BAM, followed three days later by intracisternal infection with Streptococcus pneumoniae. At 18 h post-infection, CL-treated mice exhibited clinical signs similar to controls treated with phosphate-buffered saline liposomes (PBSL). However, CL-treated mice had lower cerebrospinal fluid leukocyte counts, increased expression of brain immune mediators, and elevated plasma levels of neuronal damage (NEFL) and astrocyte activation (S100B) markers. Over a 42-h observation period - during which ceftriaxone therapy was started 18 h post-infection - CL-treated mice showed significantly worse outcomes: 9 of 12 reached termination criteria versus 1 of 9 PBSL-treated mice. This correlated with more severe neuropathology, higher bacterial loads, and persistent inflammation. Notably, infection with a pneumolysin-deficient mutant conferred strong protection against disease aggravation caused by macrophage depletion, whereas caspase-1 inhibition - despite its known immunosuppressive effects in experimental PM - did not. These findings underscore a critical immunoregulatory role for BAM in PM, particularly in resolving rather than initiating inflammation. Their absence exacerbates disease severity, mainly due to increased bacterial proliferation and elevated levels of bacterial toxins.