Pathogenesis of Acute CNS infection and injury

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Many inflammatory processes directly impact central nervous system (CNS) function and give rise to human diseases. For example, acute CNS infection can induce a variety of diseases, such as meningitis and encephalitis. A primary interest in our laboratory is to mechanistically define the impact of acute infections on the CNS and establish treatments to ameliorate the associated neurological diseases. We study viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus), parasitic (plasmodium berghei) and fungal (candida albicans) infections to determine how the immune system responds to these different challenges. We are ultimately interested in improving our immunological defenses against different pathogens, understanding why our immune system sometimes fails to protect us, and developing therapeutics that improve CNS recovery after infections are cleared. Another major focus of our laboratory is CNS injuries and the subsequent degenerative diseases that develop when the brain does not heal properly. We study the immunology of traumatic brain injuries (TBI) as well as cerebrovascular injuries (CVI) and identify therapeutics that impede acute damage and promote functional repair. Because healthy vasculature is a crucial component of CNS function, we explore and discover immunological mechanisms that promote vascular repair in the damaged brain and meninges. We also study environmental variables like infections that alter repair trajectories after CNS injuries. We use many contemporary approaches, such as intravital two-photon laser scanning microscopy (TPM), to study the neural-immune interface under states of health and disease. TPM allows us to film immune cells in the living brain and meninges. We watch the dynamics of fluorescently tagged innate (e.g., microglia, monocytes, macrophages, neutrophils, dendritic cells, innate lymphoid cells) and adaptive (e.g., microbe specific CD8+ T cells, CD4+ T cells, B cells) immune cells in the CNS under steady state or in response to perturbations like infections or injuries. We also test therapeutic compounds by administering them transcranially (through the skull bone) and then visualize in real-time how these therapeutics locally influence the inflammatory process. This powerful approach allows us to evaluate the efficacy of potential therapeutics at the site of disease. We have recently made some important discoveries in the field of cerebrovascular injury research. In humans, stroke, intracerebral damage, and TBI can all lead to vascular hemorrhaging in the brain, which is often followed by potentially life-threatening brain swelling or edema. We revealed that this edema is caused in part by massive extravasation of innate myelomonocytic cells from the blood into the brain in response to hemorrhage, and that secondary edema can be prevented by therapeutically blocking myelomonocytic cell extravasation with a combination of anti-LFA1 and anti-VLA4 antibodies. Microglia also play an important role in the cerebrovascular injury response by rapidly projecting processes that envelop damaged blood vessels and limit the extent of leakage. Pro-angiogenic microglia later participate in vascular remodeling - a process that is set into motion by classical blood monocytes. Overall, our research has informed us that the innate immune system has an essential role in repairing damaged blood vessels in the brain parenchyma and meninges following CVI. Importantly, the damaging effects of early myelomonocytic cell extravasation can be prevented with bolus anti-LFA1/VLA4 therapy while still allowing the reparative innate immune reaction to develop later. We have also recently explored the mechanistic dialogue between peripheral monocytes and microglia that is required to repair and rebuild damaged blood vessels after CVI. We quantified the distribution of pro-angiogenic VEGFA+ repair associated microglia (RAM) in the penumbrae of human stroke brain lesions as well as their proximity to damaged cortical blood vessels following CVI in rodents. We then identified a cytokine (IL-6) released by monocytes / macrophage that endowed RAM with their pro-angiogenic and proliferative properties. This cytokine induced signaling directly in microglia to promote RAM generation, thereby facilitating successful cerebrovascular repair and functional recovery. We also examined the transcriptomic landscape in myeloid cells at the single cell level, demonstrating that CVI induces multiple signaling pathways in microglia and MDM that include IL-6, TNF-, and IFN-I signaling. Notably, we observed that RAM expressed a pro-angiogenic gene signature and were highly proliferative. In the absence of IL-6 signaling or classical CCR2+ monocytes, RAM generation was impeded, resulting in failed cerebrovascular repair, a leaky BBB, neural cell death, fibrosis, and diminished functional recovery. Importantly, exogenous IL-6 treatment was able to compensate for CCR2+ monocyte deficiency by restoring RAM generation and cerebrovascular remodeling. We therefore propose that IL-6-induced VEGFA+ RAM are required for successful vascular repair and functional brain recovery following CVI. Our studies provide molecular insights into how monocytes coordinate with microglia to rebuild damaged cerebrovasculature and offer a potential therapeutic opportunity to facilitate RAM generation following CVI.