Interleukin 10 Protects the Brain Microcirculation From Spirochetal Injury

Abstract

Spirochetal infections are an important cause of neurological disease. In previous studies of the pathogenesis of spirochetal brain infection, mice inoculated with Borrelia turicatae, an agent of tick-borne relapsing fever in North America, developed mild meningitis and parenchymal activation/infiltration by interleukin 10 (IL-10)-producing microglia/macrophages. Here, we investigated the neuro-protective effects of IL-10 during spirochetal infection by comparing the outcomes of B. turicatae infection in wild-type and IL-10-deficient RAG2-deficient mice. Mice were infected with either serotype 1 (Bt1), which causes more brain infection but lower bacteremia, or Bt2, which causes less brain infection but higher bacteremia. Interleukin 10 deficiency resulted in early death from subarachnoid/intraparenchymal brain hemorrhage in Bt2-infected mice. These mice had marked apoptosis of brain microvascular endothelial cells as assessed by terminal transferase-mediated DNA nick end-labeling staining. In contrast, Bt1 infection caused milder subarachnoid hemorrhage. Neuronal apoptosis was observed in mice infected with both serotypes and was prominent in the cerebellum. Neutralization of tumor necrosis factor prevented death and reduced morbidity and brain injury in mice infected by both serotypes. We conclude that IL-10 plays a critical role protecting the cerebral microcirculation from spirochetal injury possibly by inhibition effects of tumor necrosis factor.

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

“…Previously, we had shown that the absence of IL-10 in mice unable to clear peak bacteremia results in rapid death from intracerebral hemorrhage (13,29,52). In this paper, we showed that the same occurs even during relapsing-remitting infection and that HBMEC unable to produce IL-10 are rapidly killed in as few as 20 min of incubation with 10 5 spirochetes/ml.…”

“…This was the case even after 2-3 mo of persistent infection with 10 7 -10 8 bacteria per ml blood (15,17,18). In contrast, severe cerebrovascular injury developed rapidly following the onset of peak bacteremia in mice deficient in IL-10 and unable to clear the infection (13,19). A fundamentally important protective role of IL-10 for brain endothelium was suspected by the finding of high circulating levels of IL-10 in experimentally infected mice without cerebrovascular injury (13,17) and in patients infected with Borrelia recurrentis with mild clinical disease (20).…”

“…Bt2 was chosen for this and all subsequent experiments because it causes severe brain hemorrhage in B cell-deficient mice in the absence of IL-10 (13,20). HBMEC were incubated with Bt2 for 4, 12, or 24 h at concentrations similar to peak bacteremia in WT (29) and B cell-deficient mice (9,15,16).…”

“…In contrast, severe cerebrovascular injury developed rapidly following the onset of peak bacteremia in mice deficient in IL-10 and unable to clear the infection (13,19). A fundamentally important protective role of IL-10 for brain endothelium was suspected by the finding of high circulating levels of IL-10 in experimentally infected mice without cerebrovascular injury (13,17) and in patients infected with Borrelia recurrentis with mild clinical disease (20). Brain microvascular endothelial cells are the major cellular component of the brain-blood barrier and are exposed to large numbers of circulating spirochetes during peak bacteremia.…”

“…Our laboratory has been studying the neurologic complications of bacterial infection by using a neurotropic strain of the RF spirochete Borrelia turicatae (9)(10)(11)(12)(13)(14). Several previous studies of relapsing-remitting or persistent high-level infection in mice failed to find any evidence of cerebrovascular injury (9)(10)(11)(12)(15)(16)(17).…”