Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair(1), but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the G alpha(i)-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP(+) neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10(+)TIM4(+) dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.

Automated summary

This study investigated the role of sensory neurons in promoting the tissue-repair function of macrophages and uncovered the regulatory mechanism of the neuropeptide TAFA4 on macrophage inflammatory responses. TAFA4, produced by a subset of sensory neurons, modulates the inflammatory profile of macrophages and promotes the production of IL-10 after skin damage in mice. This neuroimmune regulatory pathway driven by TAFA4 helps prevent fibrosis and promotes tissue regeneration, presenting new therapeutic perspectives for inflammatory diseases.