Blockade of the neurokinin-1 receptor in keratinocytes prevents neuroinflammation and decreases innate and adaptive immune responses in the skin

Abstract

Abstract Substance P (SP) is a proinflammatory neuropeptide that following Ag entrance in peripheral tissues signals via the neurokinin 1 receptor (NK1R) to initiate innate and support adaptive cellular immune responses. These mechanisms underlie chronic skin inflammatory disorders like contact dermatitis (CD). Here we propose to develop an immunosuppressive method to prevent and treat CD by blocking the effects of SP during skin sensitization with haptens. We utilized microneedle arrays to efficiently deliver the hapten 2,4-dinitrocholorobencene (DNCB) and NK1R antagonists simultaneously to the skin of C57/BL6 mice. This approach, restrained neuroinflammation, increased T regulatory cells and decreased the viability of Th1 and Tc1 biased cells in the draining lymph nodes. Together these effects inhibited local and systemic CD and prevented its relapses. Using the Cre-Lox P system, we demonstrate that specific deletion of the NK1R in keratinocytes but not in leukocytes inhibited the sensitization phase of CD by blocking the release of IL-1β and IL-6. Whereas deletion of the receptor in keratinocytes or in dendritic cells was necessary to abrogate the adaptive cellular immunity. Our data demonstrate the possibility of preventing the development of cellular immunity by engineering the skin microenvironment to restrain the effects of neuroinflammatory peptides accounting for the onset of chronic skin inflammatory diseases.