Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in Mammals

Abstract

Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor B. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…Moreover, evidence indicates that TLR activation is also critical for neuronal morphogenesis. In cultured dorsal root ganglion, cortical, and hippocampal neurons, treatment with poly I:C, a synthetic dsRNA, induces growth-cone collapse and inhibits neurite outgrowth [30] . The effect of poly I:C is mediated via TLR3 because neurons lacking functional TLR3 do [30,61] TLR7 ssRNA CL075, Loxoribine, R848 [11,20,21,32] let-7, miR-21, miR-29a [20,21,32] TLR8 R848 [31] ?…”

“…It should be noted that although imiquimod ( t e r m e d R 8 3 7 , a n i m i d a z o q u i n o l i n e c o m p o u n d ) , CL075 (a thiazoquinoline compound) and loxoribine (a not respond to poly I:C [30] . This study indicates that TLR3 activation plays a negative role in neurite outgrowth.…”

“…In contrast to TLR7, the signaling pathway downstream of TLR3 that controls neurite outgrowth remains to be elucidated [30] . Poly I:C treatment inhibits neurite outgrowth in a TLR3-dependent but NF-κB-independent manner [30] .…”

“…Poly I:C treatment inhibits neurite outgrowth in a TLR3-dependent but NF-κB-independent manner [30] .…”

“…In this study, MyD88 knockout neurons were also used to demonstrate that MyD88 is not involved in the TLR3 pathway [30] . However, because TLR3 delivers its signals using Trif but not MyD88, it appears to be more appropriate to examine the role of Trif rather than MyD88 in the TLR3 pathway to control neurite outgrowth.…”