Optogenetic Dissection of Sensory Neuron-Macrophage Interactions in Psoriasiform Skin Inflammation: Advances Based on...

Psoriasis represents a chronic inflammatory skin disorder driven by bidirectional neuro-immune crosstalk between cutaneous sensory neurons and tissue macrophages. Tissue-resident macrophages exhibit a continuous functional spectrum rather than rigid binary M1/M2 subsets, and their dynamic reprogramming critically shapes inflammatory onset, perpetuation and resolution; however, conventional experimental approaches cannot readily provide causal, high spatiotemporal-resolution evidence for neuron-macrophage communication in intact skin. Optogenetics combined with intravital in vivo calcium imaging has emerged as a powerful integrated platform to precisely manipulate sensory neuronal activity and simultaneously record real-time calcium signalling dynamics in macrophages. Herein, we review recent advances using this toolkit in psoriasiform skin inflammation. Optogenetic activation of nociceptive sensory neurons triggers rapid macrophage calcium transients primarily mediated by neuropeptide calcitonin gene-related peptide (CGRP). Chronic optogenetic neuronal stimulation is sufficient to initiate psoriasiform lesions, whereas optogenetic silencing can reverse established skin inflammation. Downstream calcium-CaMKII-NF-κB/MAPK cascades drive pro-inflammatory macrophage activation, while sympathetic norepinephrine-dependent β2-adrenergic receptor signalling provides homeostatic negative feedback. A spatiotemporal calcium-wave model further explains focal plaque formation. We also discuss translational bottlenecks for optogenetic techniques and potential therapeutic targets targeting sensory neuron-macrophage axis. Finally, we highlight future multimodal research directions bridging pre-clinical mechanistic findings and clinical translation for psoriasis and other neuro-immune inflammatory skin diseases.