Role of Neurokinin 1 Receptor in Modulating the Immune-Stimulatory Function of Dendritic Cells

There is a growing body of evidence indicating that the nervous and immune systems cross-talk during inflammatory and immune responses. Secretion of pro-inflammatory neuropeptides from the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), favors cellular immunity by binding the neurokinin 1 receptor (NK1R) to promote immune cell survival and activation. Dendritic cells (DCs) are essential for the stimulation of cellular immunity; however, the ability of pro-inflammatory tachykinins to affect the immune-stimulatory function of DCs remains elusive. Since DCs home strategically to peripheral and lymphoid tissues where tachykinins are secreted, we hypothesized that signaling via the NK1R enhances DC longevity and their T cell-stimulatory function, including the induction of type-1 CD4+ T cell helper (Th1) and CD8+ cytotoxic T cell (CTL/Tc1) responses. Using DCs generated from murine bone marrow precursors (BMDCs), I describe that BMDCs express functional NK1R, and agonistic signaling via the receptor rescues BMDCs from apoptosis. The immunological relevance of these findings were validated in vivo, as I demonstrate that adoptive transfer of NK1R-signaled BMDCs loaded with antigen (Ag) migrate efficiently to tissue-draining lymph nodes (DLNs) where they survive longer and induce superior type-1 DTH responses compared to adoptive transfer of control Ag-loaded BMDCs. Secondly, I investigated the mechanisms by which NK1R-signaled BMDCs favor cellular immunity, including their ability to generate Th1 and CTL/Tc1 responses. I show that agonistic signaling via the NK1R promotes the maturation of BMDCs and inhibits their secretion of IL-10, and adoptive transfer of NK1R-signaled BMDCs elicits enhanced Ag-specific Th1 and CTL/Tc1 responses. The individual roles of adoptively transferred NK1R-signaled BMDCs and endogenous DCs were further addressed by comparing the development of type-1 immunity in wild-type, IL-12 knockout (IL-12p35-/-) and Diphtheria Toxin Recetor (DTR) transgenic (inducible depletion of CD11c+ DCs) mice. With these models, I demonstrate that generation of robust Ag-specific Th1 and CTL/Tc1 responses requires secretion of IL-12p70 by endogenous DCs and inhibition of IL-10 production by transferred BMDCs. Collectively, our data strongly suggest that adoptive transfer of NK1R-signaled BMDCs promotes enhanced type-1 immunity by mechanisms involving both exogenous and endogenous DC populations

Oral delivery of il-27 recombinant bacteria attenuates immune colitis in mice

BACKGROUND & AIMS: Treatment of inflammatory bowel disease (IBD) would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine IL27, which is actively synthesized in situ by the food-grade bacterium Lactococcuslactis (LL-IL-27), and tested its ability to reduce colitis in mice. METHODS: The 2 genes encoding mouse IL27 were synthesized with optimal codon usage for L lactis and joined with a linker; a signal sequence was added to allow for secretion of the product. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(−/−) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed. RESULTS: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced numbers of CD4(+) and IL17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice following administration of dextran sodium sulfate. CONCLUSIONS: L lactis engineered to express IL27 (LL-IL-27) reduces colitis in mice, by increasing production of IL10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for IBD