Nasal solitary chemosensory cells linking irritation to inflammation

描述(申请人提供)：对呼吸道粘膜的化学刺激会引起各种反射反应，如打喷嚏、呼吸暂停、咳嗽和喉咙闭合，以保护肺部免受损害。鼻黏膜刺激还会激活炎症和局部免疫反应，以保护鼻黏膜上皮，避免影响嗅觉上皮的紊乱。吸入刺激物可以激活化学反应的自由神经末梢或孤立的化学感觉细胞(SCCs)，后者是由三叉神经支配的特殊的化学敏感的上皮细胞。SCCs表达苦味转导通路的元件，即Tas2R苦味受体、G蛋白-Gustducin、PLC2和Trpm5瞬时受体电位离子通道(Tizzano等人)。2010)。在这项建议中，我将重点放在干细胞作为免疫系统树突状细胞或巨噬细胞等周围上皮细胞功能调节器的下游作用。我将测试一种假设，即刺激物诱导的鼻部干细胞的激活会导致局部上皮细胞的免疫和/或炎症反应。其结果是，呼吸道免疫细胞能否被激活并被吸引到对化疗有反应的干细胞上，以及干细胞能否激活免疫细胞成熟并表达新的分子和功能标记物。在拟议的研究中，我们将测试吸入刺激物激活的SCC是否会引起鼻上皮的炎症反应，并确定SCC的激活是否会导致巨噬细胞和/或树突状细胞的局部反应。为了测试SCC是否对这些反应是必需的，我们将利用缺乏Trpm5(Trpm5-KO)的小鼠，Trpm5是SCC功能所必需的瞬时受体潜在阳离子通道。我们以前已经证实，这些小鼠对特定刺激物的反应性受损(Tizzano等人。2010)。然而，SCCs与周围呼吸道上皮细胞或免疫细胞的相互作用以及SCCs与刺激性暴露后的炎症之间的联系尚不清楚。为了解决这个问题，目前的提案将确定SCCs是否会在刺激性刺激下招募免疫细胞，以及SCCs是否会在刺激性刺激下导致鼻黏膜局部炎症反应。这些研究将为上皮细胞，即干细胞，作为一种KE受体细胞，参与对刺激性化合物的局部炎症和免疫反应提供第一个证据。 公共卫生相关性：上呼吸道的化疗敏感性在哮喘和上呼吸道疾病中起着重要作用。吸入刺激物可以激活化学敏感的游离神经末梢或三叉神经支配的孤立化学感觉细胞(SCCs)来触发反应。化学刺激引起呼吸道粘膜的各种变化，包括炎症/免疫反应和呼吸反射。拟议的研究将确定鳞状细胞癌激活是否会导致鼻黏膜的炎症和/或局部免疫反应。

DESCRIPTION (provided by applicant): Chemical irritation of airway mucosa elicits a variety of reflex responses such as sneezing, apnea, coughing and laryngeal closure aimed to protect the lungs from damage. Nasal mucosa irritation also activates inflammatory and local immune responses aimed to protect the nasal epithelium and avoid disorders affecting the olfactory epithelium. Inhaled irritants can activate either chemo-responsive free nerve endings or solitary chemosensory cells (SCCs) which are specialized chemo-sensitive epithelial cells innervated by the trigeminal nerve. SCCs express elements of the bitter taste transduction cascade, i.e. Tas2R bitter taste receptors, G- protein -gustducin, PLC2 and the TrpM5 transient receptor potential ion-channel (Tizzano et al. 2010). In this proposal, I focus on the downstream action of SCCs as modulators of function of the surrounding epithelial cells including dendritic or macrophage cells of the immune system. I will test the hypothesis that irritant- induced activation of nasal SCCs leads to an immune and/or inflammatory response in the local epithelium. A consequence of that is whether the airway immune cells can be activated and attracted to the chemo-responsive SCCs, and whether SCC excitation activates the immune cells to mature and express new molecular and functional markers. In the proposed studies we will test whether activation of SCCs by an inhaled irritant causes an inflammatory response of the nasal epithelium and determine if SCC activation leads to a local response by macrophages and/or dendritic cells. In order to test whether SCCs are necessary for these responses, we will utilize mice that lack TrpM5 (TrpM5-KO), a transient receptor potential cation channel necessary for SCC function. We previously established that these mice have impaired responsiveness to particular irritants (Tizzano et al. 2010). However, the interactions of SCCs with the surrounding respiratory epithelial or immune cells and the link between SCCs and inflammation after irritant exposure are not understood. To address this issue, the current proposal will determine whether immune cells are recruited by the SCCs in response to an irritant stimulus and whether in response to irritants, the SCCs will lead to a local inflammatory response of the nasal epithelium. These studies will provide the first evidence for an epithelial cell, the SCCs, as a ke receptor cell involved in the local inflammatory and immune responses to irritant compounds. PUBLIC HEALTH RELEVANCE: Chemo-sensitivity of the upper respiratory tract plays an important role in asthma and upper respiratory diseases. Inhaled irritants can activate either chemo-sensitive free nerve endings or trigeminally innervated solitary chemosensory cells (SCCs) to trigger a response. Chemical irritation of the airway mucosa elicits a variety of changes including inflammatory/immune responses as well as respiratory reflexes. The proposed studies will determine whether SCC activation leads to an inflammatory and/or local immune response in the nasal mucosa.