Beyond defense: regulation of neuronal morphogenesis and brain functions via Toll-like receptors

Abstract

Toll-like receptors (TLRs) are well known as critical pattern recognition receptors that trigger innate immune responses. In addition, TLRs are expressed in neurons and may act as the gears in the neuronal detection/alarm system for making good connections. As neuronal differentiation and circuit formation take place along with programmed cell death, neurons face the challenge of connecting with appropriate targets while avoiding dying or dead neurons. Activation of neuronal TLR3, TLR7 and TLR8 with nucleic acids negatively modulates neurite outgrowth and alters synapse formation in a cell-autonomous manner. It consequently influences neural connectivity and brain function and leads to deficits related to neuropsychiatric disorders. Importantly, neuronal TLR activation does not simply duplicate the downstream signal pathways and effectors of classical innate immune responses. The differences in spatial and temporal expression of TLRs and their ligands likely account for the diverse signaling pathways of neuronal TLRs. In conclusion, the accumulated evidence strengthens the idea that the innate immune system of neurons serves as an alarm system that responds to exogenous pathogens as well as intrinsic danger signals and fine-tune developmental processes of neurons.

Keywords: Innate immunity; Neuronal development; TLR.

Fig. 1

Schematic of the protein domain structure of TLRs. TLR3 is used as an example here. Binding of double-stranded RNA (dsRNA) induces TLR3 dimerization, leading to activation of downstream signaling. LRRs, leucine-rich repeats; TIR, Toll/interleukin-1 receptor; TM, transmembrane domain. Proteolysis to cleave the ectodomain is also involved in TLR3 activation, but it is not indicated here

Fig. 2

Classical TLR signaling pathways. MYD88 and TRIF are two major TIR domain-containing adaptors downstream of TLRs. IRFs, NF-κB and AP1 are three common downstream transcriptional factors in TLR pathways that regulate gene expression. Detailed descriptions are provided in the main text

Fig. 3

Non-classical TLR signaling pathways. a Three different endosomal TLRs use MYD88 to activate different pathways to fine-tune neuronal morphology. b TLR2 activates downstream signaling via TRIF in macrophages. c TLR5 can also use TRIF to deliver signal. d Different concentrations of ligand activate different TLR9 pathways in dendritic cells. e In addition to MYD88, TLR7 and TLR9 also use SARM1 to trigger cell death of neurons

Fig. 4

Comparison of TLR7 and TLR8 in terms of ligand binding, signaling pathways and their downstream effectors. Details are provided in the main text

Fig. 5

The action of neuronal TLRs during brain development. a During the first two postnatal weeks in the rodent brain, axon and dendrite outgrowth, as well as synapse formation, take place to establish connections and to build a functional brain. b Programmed cell death also occurs at the same time. DAMPs—including dsRNAs, ssRNAs, and apoptotic bodies—released from the dead neuron can activate TLRs in adjacent neurons. When those adjacent neurons receive the damage signals, they temporarily withdraw their dendrites to avoid growing into an unhealthy environment. The innervated axons from distal neurons likely also sense those damage factors and retract to prevent forming connections to a dead neuron. Meanwhile, activation of TLRs in neurons triggers local release of low levels of inflammatory cytokines and chemokines to attract nearby microglia. After entering the damaged zone, activated microglia engulf the remaining dead neuronal areas. c Once microglia have cleaned up the damaged area, adjacent neurons may regrow their dendrites. Axons projected from distal neurons may also resume extension to find their targets. d Later, the whole system is stabilized and the proper circuitry is established