IFN‐γ elevates airway hyper‐responsiveness via up‐regulation of neurokinin A/neurokinin‐2 receptor signaling in a severe asthma model

Abstract

The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-c. The administration of IFN-c instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1 À/À mice after stimulation with IFN-c. In addition, methacholine-mediated Ca 21 influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-c-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-c directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma.

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

“…Then, we found that the Th2-mediated asthma model was steroid sensitive, but the Th1 and Th17 models were steroid resistant, suggesting that both Th1 and Th17 cause steroid-resistant severe airway inflammation. Furthermore, we performed intranasal injection with IFN-g and confirmed the direct effect of IFN-g on the increased AHR (11). Then, we demonstrated that the expression level of neurokinin-2 receptor (NK2R) was remarkably enhanced in the Th1-dependent asthma models and in the lung after IFN-g injection.…”

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

“…IFN-␥ from Th1 cells is required for the induction of severe airway hyperresponsiveness (30). Furthermore, we demonstrated that resveratrol inhibits TLR3 signaling, M2R expression, and IFN-␥ production.…”

“…The activation of cytokines, chemokines, and IFNs in the host after binding viral PAMPs leads to an antiviral state and activates the adaptive immune response. Upon RSV infection, the signal initiated from TLR3 and TLR4 activates the adaptor protein TRIF (7,27,30). Specifically, the RSV fusion protein can bind to TLR4, which induces the production of interleukin-1␤ (IL-1␤), IL-6, IL-8, and tumor necrosis factor alpha (TNF-␣) (38).…”

“…Importantly, TRIF-dependent signaling is associated with IFN-␥ production (49). Recent reports suggest that IFN-␥ produced by Th1 cells is required in the induction of severe AHR (30). During RSV infection, TRIF-dependent signaling was induced and the lanes 1 to 3).…”

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

“…Previously, we demonstrated that neuropeptide signaling through NK2R was correlated with airway hyperresponsiveness in mouse severe asthma models. 3 Moreover, we found that the NKA-NK2R signaling pathway was involved in the antigen-presenting function of murine dendritic cells (DCs) and that NK2R expression on DCs was enhanced by Ohtake 8 IFN- and LPS stimulation in a STAT-1-dependent manner. 4 Additionally, we confirmed that human DCs significantly upregulated gene expression levels of NK2R and TAC-1, which encoded Substance P and Neurokinin A, after IFN- or poly I:C stimulation, suggesting possible roles of neuropeptide signaling in human DCs.…”