Autocrine secretion of hemokinin-1 promotes the innate immunostimulatory function of mast cells. (177.21)

Abstract

Abstract Mast cells (MC), with pro- and anti-inflammatory functions, control innate and adaptive immune responses. Mechanisms causing such disparate functions are only starting to be elucidated. Recent advances in neuroimmune regulation suggest that MC function may be regulated, in part, by neuropeptides. MC express the neurokinin-1 receptor (NK1R), the preferred receptor for the inflammatory neuropeptides, Substance P (SP) and Hemokinin-1 (HK1). We hypothesized that agonistic signaling through the NK1R regulates MC function. We compared the ability of C57BL/6 wild type (WT) or NK1RKO bone marrow-derived MC stimulated via FcϵRI or TLR4 to secrete pro-inflammatory IL-1β, IL-6, IL-33, and TNFα, or anti-inflammatory, IL-10. NK1RKO MC secreted significantly less TNFα and IL-33 but equal levels of IL-10, IL-6 and IL-1β compared to WT-MC, results that were further confirmed with WT-MC incubated with the NK1R antagonist L760,330. As our experimental conditions lack nerve fibers and exogenous SP or HK1 did not increase cytokine secretion we postulated that the observed effects were caused by autocrine secretion of NK1R agonists by MC. Using quantitative RT-PCR, we found high expression of the tac4 gene encoding for HK1 which was further increased following MC stimulation while the levels of SP mRNA remained significantly lower in spite of MC simulation. Together our results demonstrate that autocrine HK1 and NK1R signaling are potent stimulators of the pro-inflammatory function of MC.