Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity

Abstract

IntroductionBecause of their crucial role in initiation and control of innate and adaptive immunity, myeloid dendritic cells (DCs) are the preferred target Ag-presenting cells for positive cellular vaccination protocols. 1 During the past decade, ex vivo-generated DCs have been used in immunization approaches for prevention and treatment of cancer and infectious diseases. 2 Current DC-based vaccines focus on the adjuvant effect of proinflammatory mediators, conferring DCs the capability to initiate and bias T-cell immune responses. [3][4][5] However, despite initial promising results, DC-based vaccines do not always elicit potent T-cell immunity. 6 Generation of efficient T-cell immunity using ex vivo-generated DCs requires a critical number of adoptively transferred DCs capable of surviving apoptosis. 7 Indeed, DCs used as cellular vaccines are exposed to proapoptotic stimuli at the injection sites and in tissue-draining lymph nodes (DLNs). 7,8 Accordingly, exposure of DCs to proapoptotic stimuli triggered by lytic infections, ultraviolet B (UVB) irradiation, tumor mediators, and cytotoxic cells results in immune suppression. 9 In addition, interaction of DCs with cells in early apoptosis down-regulates the T cellstimulatory ability of DCs and induces immunological tolerance. [10][11][12][13] Conversely, proinflammatory mediators and growth factors promoting DC survival, including granulocyte macrophagecolony stimulating factor (GM-CSF), 14 prostaglandin E 2 (PG-E 2 ), 15 lipopolysaccharide (LPS), 16 and CCR7 17 and CD40 18 ligands, correlate with enhanced T-cell immunity.The intracellular signaling involved in DC survival is currently being elucidated. Activation through CD40 promotes DC survival by favoring a positive balance of nuclear factor kappa B (NF-B) versus activator protein-1 (AP-1) pathway, 19 whereas GM-CSF, LPS, and PG-E 2 prevent DC apoptosis by signaling via phosphatidylinositol 3-kinase (PI3K) and protein kinase B (referred as Akt). 14,15,20 In contrast, the immune-suppressive drug rapamycin induces DC death by antagonizing GM-CSF signaling via inhibition of the PI3K-Akt signaling cascade. 14,21 Recently, it has become evident that the outcome of the immune response is highly regulated by neuropeptides. The balance between anti-inflammatory and proinflammatory neuropeptides is crucial to maintain the immune privilege of the central nervous system (CNS) and the steady-state condition in peripheral tissues, and altering this delicate balance plays a relevant role in the pathogenesis of chronic inflammatory and autoimmune diseases. [22][23][24][25][26] Proinflammatory neuropeptides such as substance P (SP) favor CD4 ϩ T helper (Th)1 bias and cellular immunity, whereas vasoactive intestinal peptide promotes CD4 ϩ Th2 bias. 27-34 Conversely, calcitonin gene-related peptide and the anti-inflammatory products of proopiomelanocortin cleavage, ␣-melanocyte-stimulating hormone and adrenocorticotropin, are potent suppressors of cellular immunity. 23 The proinflammatory tachykinins SP and hemokinin-1 (HK-1...

Hemokinin-1 Activates the MAPK Pathway and Enhances B Cell Proliferation and Antibody Production

“…Consistent with this notion, we were able to detect NK-1 but not NK-2 or NK-3 mRNA in B cells (data not shown). Like in many other assays (21,23,25,26,42,43), HK-1 activity on B cells could be fully reproduced with SP, which is in accord with several earlier reports documenting enhanced Ig secretion in the presence of SP (44). Given the apparent functional overlap, an important issue is the tissue distribution of the two peptides.…”

“…Other than Ca 2+ mobilization, little is known about HK-1 signaling. Several studies have demonstrated that SP or its analog induced ERK phosphorylation, protein kinase C translocation, or the activation of the PI3K-Akt pathway in different cell types (43,48). In this study, we showed that HK-1 was a potent activator of the MAPKs in B cells.…”

“…More recently, Janelsins and colleagues demonstrated that both HK-1 and SP rescued bone marrow-derived dendritic cells (DCs) from apoptosis induced by the deprivation of growth factors, probably by activating the PI3K-Akt pathway. Furthermore, they showed that NK-1-signaled DCs exhibited increased longevity in vivo, leading to enhanced and prolonged effector cellular immunity (43).…”

Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor

“…The NK-1 receptor, the preferred receptor of SP, mediates a variety of physiological and pathophysiological responses (22,23,43). Although previous studies have confirmed that SP enhances corneal epithelial migration when combined with IGF-1 or EGF (41,44,45), the exact mechanism remains unclear.…”

“…Moreover, SP causes the mobilization of bone marrowderived stem cells to participate in corneal wound healing (19,20). Interestingly, recent evidences have shown that SP activates the EGFR, mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), and phosphoinositide 3-kinase-Akt (PI3K-Akt) signaling pathways, as well as promotes the healing of inflamed colonic epithelium (21) and possesses antiapoptotic effects in colonocytes (22), dendritic cells (23), tenocytes (24), neutrophils (25), and bone marrow-derived stem cells (26).…”