Background: Recent studies have indicated that Toll-like receptor 4 (TLR4), a pathogen-recognition receptor that\ntriggers inflammatory signals in innate immune cells, is also expressed on sensory neurons, implicating its putative\nrole in sensory signal transmission. However, the possible function of sensory neuron TLR4 has not yet been\nformally addressed. In this regard, we investigated the role of TLR4 in itch signal transmission.\nResults: TLR4 was expressed on a subpopulation of dorsal root ganglia (DRG) sensory neurons that express TRPV1.\nIn TLR4-knockout mice, histamine-induced itch responses were compromised while TLR4 activation by LPS did not\ndirectly elicit an itch response. Histamine-induced intracellular calcium signals and inward currents were comparably\nreduced in TLR4-deficient sensory neurons. Reduced histamine sensitivity in the TLR4-deficient neurons was\naccompanied by a decrease in TRPV1 activity. Heterologous expression experiments in HEK293T cells indicated\nthat TLR4 expression enhanced capsaicin-induced intracellular calcium signals and inward currents.\nConclusions: Our data show that TLR4 on sensory neurons enhances histamine-induced itch signal transduction\nby potentiating TRPV1 activity. The results suggest that TLR4 could be a novel target for the treatment of enhanced\nitch sensation.
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