Nasal solitary chemosensory cells linking irritation to inflammation

描述（由申请人提供）：化学刺激气道粘膜引起各种反射反应，如打喷嚏、呼吸暂停、咳嗽和喉闭，目的是保护肺部免受损害。鼻黏膜刺激也激活炎症和局部免疫反应，目的是保护鼻上皮，避免影响嗅觉上皮的疾病。吸入刺激物可以激活无化学反应神经末梢或孤立化学感觉细胞（SCCs）， SCCs是由三叉神经支配的特化化学敏感上皮细胞。SCCs表达苦味转导级联的元件，即Tas2R苦味受体、G- protein -gustducin、PLC2和TrpM5瞬时受体电位离子通道（Tizzano et al. 2010）。在本提案中，我将重点关注SCCs作为周围上皮细胞（包括免疫系统的树突状细胞或巨噬细胞）功能调节剂的下游作用。我将测试刺激诱导的鼻腔SCCs激活导致局部上皮免疫和/或炎症反应的假设。其结果是气道免疫细胞是否可以被激活并吸引到化学反应性SCC，以及SCC兴奋是否激活免疫细胞成熟并表达新的分子和功能标记。在拟议的研究中，我们将测试吸入刺激物激活SCC是否会引起鼻上皮的炎症反应，并确定SCC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是否为这些反应所必需，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电位阳离子通道。我们先前确定这些小鼠对特定刺激物的反应受损（Tizzano et al. 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与刺激暴露后炎症之间的联系尚不清楚。为了解决这个问题，目前的建议将确定免疫细胞是否在刺激刺激下被SCCs招募，以及SCCs是否在刺激刺激下导致鼻上皮局部炎症反应。这些研究将为上皮细胞（SCCs）作为一种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。

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.