Substance P-NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis

Sumeet Manandhar; Mohna Bandyopadhyay; Olga Tkacheva; William Shufesky; Greg Gibson; Simon C. Watkins; Adrian Morelli; Adriana T. Larregina

doi:10.1172/jci.insight.205826

Substance P-NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis

Sumeet Manandhar,¹ Mohna Bandyopadhyay,¹ Olga Tkacheva,¹ William Shufesky,² Greg Gibson,³ Simon C. Watkins,³ Adrian Morelli,² and Adriana T. Larregina¹

Published September 1, 2026 - More info

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Abstract

Allergic contact dermatitis (ACD), a recurrent inflammatory skin disorder, affects 21% of humans and is the second leading cause of occupational diseases in USA. ACD is initiated by the innate immune response to skin-contact sensitizers potentiated by the neuropeptide substance P (SP). Skin sensitizers stimulate SP-secreting sensory nerves and trigger proinflammatory functions of keratinocytes expressing the neurokinin 1 receptor (NK1R). Nevertheless, the neuroimmune regulation of hapten-initiated skin inflammation, remains incompletely elucidated. Using K14Cre/+NK1R^KO mice skin-sensitized with 2,4-dinitrochlorobenzene (DNCB), we demonstrate that NK1R deletion exclusively in keratinocytes prevents hapten-initiated skin inflammation, impairs the mobilization of conventional dendritic cells (cDC) to draining lymph nodes (dLN) and blocks the elicitation of the contact hypersensitivity reaction (CHS) to the same extent observed in global Tac1KO (without SP) and NK1R^KO mice. The DNCB effects were restored by skin co-administration of IL-1β and TNF-α. SP-NK1R signaling of mouse and human keratinocytes increased transcripts encoding proteins of the NLRP3 inflammasome. Although, DNCB and SP induced pro-IL-1β synthesis, only SP triggered intracellular Ca²⁺ increase, NFATc1 nuclear translocation and TNF-α synthesis, a cytokine mediating systemic inflammation in ACD. Our data identifying SP-NK1R-signaling of keratinocytes as a key mechanism for ACD provide relevant insight for therapies targeting skin neuroimmune interactions.

Substance P-NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis

Sumeet Manandhar,¹ Mohna Bandyopadhyay,¹ Olga Tkacheva,¹ William Shufesky,² Greg Gibson,³ Simon C. Watkins,³ Adrian Morelli,² and Adriana T. Larregina¹

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Substance P-NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis

Sumeet Manandhar,1 Mohna Bandyopadhyay,1 Olga Tkacheva,1 William Shufesky,2 Greg Gibson,3 Simon C. Watkins,3 Adrian Morelli,2 and Adriana T. Larregina1

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Sumeet Manandhar,¹ Mohna Bandyopadhyay,¹ Olga Tkacheva,¹ William Shufesky,² Greg Gibson,³ Simon C. Watkins,³ Adrian Morelli,² and Adriana T. Larregina¹