The skin represents both the frontline of defence against external threats, and the largest sensory
organ of touch. Beyond its fundamental role in transmitting information to the brain, the somatosensory nervous system has become central to understand skin homeostasis. We recently described a new mechanism by which a subset of sensory neurons (GINIP+) and dermal-resident macrophages (DRMf) synergized to protect the skin from UV-induced skin damage (Hoeffel et al., Nature 2021). More recently, we also observed the involvement of the hypothalamus-pituitary-adrenal (HPA) axis in orchestrating immune cell responses to skin damages, suggesting an integral Brain-to-Skin communication system constantly tuning its integrity.
 
Confocal microscopy and light sheet imaging highlighted that TIM4+ DRMf were embedded in a neuro-vascular niche controlling neutrophil infiltration upon UV-skin injury. We are currently addressing the local transcriptomic and proteomic regulation of DRMf by GINIP+ sensory neurons through CITEseq analysis. We also detected an acute release of endogenous Glucocorticoids (GCs) in the bloodstream, suggesting the involvement of the central stress pathway. To unravel the neuronal circuits relaying DAMPs sensing from skin lesions to the brain, we mapped the activated areas using c-Fos staining, revealing the activation of paraventricular nucleus (PVN) neurons in the hypothalamus. These neurons initiated the HPA cascade, leading to GCs production by adrenal glands. We then identified key regulatory functions of GCs during the skin healing process. First, GCs promoted the expansion of myeloid precursors with pro-repair potential directly in the bone marrow. Second, by mapping circulating monocyte’s fate, and conditional depletion of the GC receptor (encoded by Nr3c1) in different myeloid compartments, we revealed the regulatory action of GCs on monocyte-derived inflammatory Mf when infiltrating the skin lesion.
 
Deciphering the nature of peripheral and central neuronal circuits promoting tissue-repair properties of resident Mf will provide new leads for regenerative medicine in various skin conditions.