Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12.
Substance-P and hemokinin-1 are proinflammatory neuropeptides with potential to promote type 1 immunity through agonistic binding to neurokinin-1 receptor (NK1R). Dendritic cells (DCs) are professional antigen-presenting cells that initiate and regulate the outcome of innate and adaptive immune responses. Immunostimulatory DCs are highly desired for the development of positive immunization techniques. DCs express functional NK1R; however, regardless of their potential DC-stimulatory function, the ability of NK1R agonists to promote immunostimulatory DCs remains unexplored. Here, we demonstrate that NK1R signaling activates therapeutic DCs capable of biasing type 1 immunity by inhibition of interleukin-10 (IL-10) synthesis and secretion, without affecting their low levels of IL-12 production. The potent type 1 effector immune response observed following cutaneous administration of NK1R-signaled DCs required their homing in skin-draining lymph nodes (sDLNs) where they induced inflammation and licensed endogenous-conventional sDLN-resident and -recruited inflammatory DCs to secrete IL-12. Our data demonstrate that NK1R signaling promotes immunostimulatory DCs, and provide relevant insight into the mechanisms used by neuromediators to regulate innate and adaptive immune responses.
Department of Dermatology, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA 15213, USA.
Brian M
BM
Janelsins
Tina L
TL
Sumpter
Olga A
OA
Tkacheva
Darling M
DM
Rojas-Canales
Geza
G
Erdos
Alicia R
AR
Mathers
William J
WJ
Shufesky
Walter J
WJ
Storkus
Louis D
LD
Falo
Adrian E
AE
Morelli
Adriana T
AT
Larregina
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology*; D007114:Immunization / Q000379:methods; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D046912:Multiprotein Complexes; D018040:Receptors, Neurokinin-1; D016753:Interleukin-10; D018664:Interleukin-12; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases