p75^NTR regulates brain mononuclear cell function and neuronal structure in <i>Toxoplasma</i> infection‐induced neuroinflammation

Abstract

Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75^NTR ) signaling. The p75^NTR is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75^NTR on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii (T. gondii) infection-induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75^NTR upon infection in wild-type mice. Although cell recruitment and phagocytic capacity of p75^NTRexonIV knockout (p75^-/- ) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75^-/- mice upregulated the production of the cytokines interleukin (IL)-10, IL-6 as well as IL-1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75^NTR , were highly increased upon chronic infection in the brain of wild-type and p75^-/- mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation-induced changes in spine density were rescued in the p75^-/- mice. In conclusion, these findings indicate that neurotrophin signaling via the p75^NTR affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.