HLA-G - LILRB - SHP2 Axis in Airway Smooth Muscle

描述（由申请人提供）： 摘要哮喘性人类气道平滑肌（HASM）与正常HASM至少在三个方面不同--收缩失调、肌细胞肥大和异常趋化因子表达--但对这些哮喘性HASM表型的机制仍知之甚少。我们已经发现，已知调节免疫系统应答的HLA-G - LILRB - SHP信号通路也在HASM中起作用。重要的是，通过该途径的信号传导促进上述哮喘HASM特征中的每一个。该建议的主要目的是分析HASM中该通路的炎症和遗传调节，以确定预防或逆转这些哮喘HASM表型的新策略。在初步研究中，我们发现LILRB 1、LILRB 2及其家族成员LILRB 4和SHP 2（但不包括SHP 1）均在人ASM中表达; LILRB受体激活人气道肌细胞内的SHP 2;并且SHP 2增加收缩力和弹性，刺激Akt信号传导和肥大，并激活NF：B和趋化因子加工。因此，HLA-G - LILRB -SHP 2信号传导通路在HASM中是完整的，并且其活化将哮喘样表型赋予气道肌肉。此外，HLA-G - LILRB -SHP 2轴在哮喘中可能异常地增强，因为：可溶性HLA-G在哮喘受试者的BAL液中比正常志愿者多三倍;并且该途径的每个组分（HLA-G、LILRB 1、LILRB 2、LILRB 4和PTPN 11，其编码SHP 2）中的遗传变异与哮喘和/或支气管高反应性相关。总之，这些数据表明了新的和生物学上合理的假设，即过度活跃的HLA-G - LILRB -SHP 2信号传递赋予哮喘HASM表型，并且干扰该信号传导途径的治疗干预可能改善哮喘中的ASM异常。为了验证这些假设，我们提出：1）确定选择的免疫调节分子如何影响正常和哮喘HASM中的HLA-G - LILRB -SHP 2信号传导; 2）评估与BHR或哮喘相关的LILRB 1、LILRB 2或LILRB 4的遗传变异如何影响正常或哮喘HASM中的HLA-G - LILRB -SHP 2信号传导;以及3）描述改变的SHP 2信号传导导致正常HASM获得哮喘HASM表型的分子机制。这些研究将揭示HLA-G - LILRB -SHP 2信号传导如何调节ASM功能;哪些遗传和炎症机制调节该调节作用;以及抑制该途径是否可以预防或逆转哮喘HASM表型的获得。(End摘要）

DESCRIPTION (provided by applicant): ABSTRACT Asthmatic human airway smooth muscle (HASM) differs from normal HASM in at least three ways - dysregulated contraction, myocyte hypertrophy, and abnormal chemokine elaboration - but the mechanisms that un- derlie these asthmatic HASM phenotypes remain poorly understood. We have discovered that the HLA-G - LILRB - SHP signaling pathway, which is known to regulate immune system responses, also operates in HASM. Importantly, signaling through this pathway promotes each of the asthmatic HASM characteristics listed above. The major objective of this proposal is to analyze the inflammatory and genetic regulation of this path- way in HASM in order to identify novel strategies that prevent or reverse these asthmatic HASM phenotypes. In preliminary studies, we found that LILRB1, LILRB2, and their family member LILRB4, and SHP2 (but not SHP1) are all expressed in human ASM; that LILRB receptors activate SHP2 within human airway myocytes; and that SHP2 increases the force of contraction and elasticity, stimulates Akt signaling and hypertrophy, and activates NF:B and chemokine elaboration. Thus, the HLA-G - LILRB - SHP2 signaling pathway is intact in HASM, and its activation imparts asthma-like phenotypes to airway muscle. Furthermore, the HLA-G - LILRB - SHP2 axis may be abnormally exaggerated in asthma because: soluble HLA-G is three times more abundant in BAL fluid of asthmatic subjects than normal volunteers; several immunomodulatory molecules found in asthmatic airways can increase LILRB expression; and genetic variations in each component of this pathway (HLA-G, LILRB1, LILRB2, LILRB4, and PTPN11, which encodes SHP2) are associated with asthma and/or bronchial hyperresponsiveness. Together, these data suggest the novel and biologically plausible hypotheses that overactive HLA-G - LILRB - SHP2 signaling imparts an asthmatic HASM phenotype, and that therapeutic intervention to interfere with this signaling pathway might ameliorate ASM abnormality in asthma. To test these hypotheses, we propose to: 1) determine how selected immunomodulatory molecules influence HLA-G - LILRB - SHP2 signaling in normal and asthmatic HASM; 2) evaluate how genetic variations in LILRB1, LILRB2, or LILRB4 that are associated with BHR or asthma influence HLA-G - LILRB - SHP2 signaling in normal or asthmatic HASM; and 3) delineate the molecular mechanisms by which altered SHP2 signaling causes normal HASM to acquire an asthmatic HASM phenotype. These studies will reveal how HLA-G - LILRB - SHP2 signaling regulates ASM function; which genetic and inflammatory mechanisms modulate that regulatory role; and whether inhibition of this pathway can prevent or reverse acquisition of the asthmatic HASM phenotype. (End of Abstract)