From Immunity to Neurogenesis: Toll-like Receptors as Versatile Regulators in the Nervous System

Abstract

Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.

Keywords: TLR; behavior; blood–brain barrier; brain; cognition; neurodegeneration; neurogenesis; neuroinflammation.

Figure 1

TLR-mediated signaling. Activation of TLRs can induce different signaling pathways. The most common signaling pathway induced by TLRs is the MyD88-dependent pathway (a). Although TLR10 has been shown to interact with MyD88, the complete signaling pathway has not been demonstrated experimentally. The MyD88-independent pathway is induced only by the activation of TLR4 and TLR3 (b). The signaling cascade culminates with the activation of transcription factors that, in turn, induce the expression of genes involved in various processes, including the immune response. Created with BioRender.com.

Figure 2

Schematic representation of the BBB located in the central part of the NVU. A cross-section of a blood vessel of the blood–brain barrier is depicted, showing the three main cell types that compose it (endothelial cells, pericytes, and astrocytes), other cell types of the neurovascular unit (microglia and neurons), and their respective TLRs that are expressed. The main function of the neurovascular unit is the formation of the blood–brain barrier and neurovascular coupling. Created with BioRender.com.

Figure 3

Roles and expression of TLRs in neurogenesis. Schematic representation of the principal stages of neurogenesis and the Toll-like receptors involved in the up- and downregulation of each process. Created with BioRender.com.