p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma 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.

Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions duringToxoplasma gondiiinfection

“…Finally, there may be other, as yet undetermined, signals that induce monocyte infiltration into the brain as a consequence of T. gondii infection but not as a direct response to the invading parasites. In chronic T. gondii models, Ly6C hi monocytes infiltrating the CNS do not express classic markers of phagocytic cells, such as TREM2 and F4/80 (23,54), although it has been shown that Ly6C hi cells can differentiate into more phagocytic Ly6C lo cells, with the potential to contribute directly to parasite clearance (23,55). Ly6C hi cells were detected in both the hippocampus and the cortex during chronic infection (23,55).…”

“…In chronic T. gondii models, Ly6C hi monocytes infiltrating the CNS do not express classic markers of phagocytic cells, such as TREM2 and F4/80 (23,54), although it has been shown that Ly6C hi cells can differentiate into more phagocytic Ly6C lo cells, with the potential to contribute directly to parasite clearance (23,55). Ly6C hi cells were detected in both the hippocampus and the cortex during chronic infection (23,55). Additionally, in a mouse model of Alzheimer's disease, chronic T. gondii infection resulted in increased clearance of plaque-forming Aβ, an outcome attributed to the phagocytic contribution of Ly6C hi monocytes (54).…”

The regulatory role of ProBDNF in monocyte function: Implications in Stanford type‐A aortic dissection disease

“…Experimental studies have reported that proBDNF signaling regulates the monocyte/macrophage/microglia functions and contributes to inflammatory responses in spinal cord injury, infection, or chemical insults. [7][8][9]26 However, all of the studies are from animal experimental studies, thus it is necessary to identify the immune-modulatory role of proBDNF in the inflammatory diseases in human. In the cultured human PBMCs and monocytes systems, our study demonstrated that proBDNF regulated the functions of monocytes and contributed to the disease progress of AAD.…”

“…In the spinal cord injury mouse model, proBDNF was found to play a detrimental role in spinal injury by regulating ED1 + macrophage infiltration and migration . In addition, in Toxoplasma infection‐induced neuroinflammation, proBDNF signaling in macrophage/microglia contributes to the recruitment of peripheral immune cells to the brain . ProBDNF and p75 NTR are highly upregulated in the peripheral blood mononuclear cells (PBMCs) of patients with major depressive disorder and in patients with alcoholism .…”

“…8 In addition, in Toxoplasma infection-induced neuroinflammation, proBDNF signaling in macrophage/microglia contributes to the recruitment of peripheral immune cells to the brain. 9 ProBDNF and p75 NTR are highly upregulated in the peripheral blood mononuclear cells (PBMCs) of patients with major depressive disorder 10 and in patients with alcoholism. 11 These studies strongly indicate a regulatory role for proBDNF in innate immune cells upon the immune response.…”