Abstract
Allergic contact dermatitis (ACD), a recurrent inflammatory skin disorder, affects 21% of humans and is the second leading cause of occupational diseases in the United States. 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/+ NK1RKO 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 to draining lymph nodes, and blocks the elicitation of the contact hypersensitivity reaction to the same extent observed in global Tac1KO (without SP) and NK1RKO 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 synthesis of TNF-α, 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.
Authors
Sumeet Manandhar, Mohna Bandyopadhyay, Olga A. Tkacheva, William J. Shufesky, Gregory A. Gibson, Simon C. Watkins, Adrian E. Morelli, Adriana T. Larregina
Figure 7
TNF-α and IL-1β restore the innate and adaptive immune response of DNCB CHS in
