Cutaneous inflammatory and pruritus pathways in keratinocytes, immune cells, and sensory nerves

The cutaneous inflammatory and pruritus pathways represent a complex neuro-immune-cutaneous system (NICS) characterized by bidirectional communication between keratinocytes, immune cells, and peripheral sensory neurons. Keratinocytes act as the first line of defense, releasing alarmins and cytokines such as TSLP and IL-33 in response to environmental triggers, which subsequently activate local immune cells and C-fiber sensory nerves (PMID: 29330110). Immune cells, particularly Th2 cells and mast cells, release pruritogenic mediators like Interleukin-31 (IL-31), which directly binds to the IL-31 receptor complex on sensory neurons to transmit the sensation of itch to the central nervous system (PMID: 15220915). This interaction establishes a self-perpetuating itch-scratch cycle that exacerbates skin barrier dysfunction and chronic inflammation. Modern therapeutic strategies target specific nodes within this network, such as the IL-4/IL-13 signaling axis or the IL-31 receptor, to provide relief from both the inflammatory lesions and the debilitating pruritus associated with conditions like atopic dermatitis and prurigo nodularis (PMID: 31607355).

Other names

Neuro-immune-cutaneous systemNICSItch-scratch cycleCutaneous neurogenic inflammationNeuro-immune crosstalk in skin

Therapeutic intervention involves the inhibition of Type 2 cytokines (IL-4, IL-13), the blockade of the pruritogenic cytokine IL-31 and its receptor (IL-31RA), the inhibition of Janus kinase (JAK) signaling pathways, or the modulation of neuro-sensory receptors (e.g., kappa-opioid receptors) to interrupt the pathological signaling between skin cells, immune cells, and the nervous system (PMID: 33005556, PMID: 29330110).