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

描述(由申请人提供)： 摘要哮喘人气道平滑肌(HASM)与正常HASM至少在三个方面不同--收缩失调、心肌细胞肥大和趋化因子异常分泌--但这些哮喘HASM表型背后的机制尚不清楚。我们发现，人类白细胞抗原-G-LILRB-SHP信号通路在HASM中也起作用，它是已知的调节免疫系统反应的信号通路。重要的是，通过这一途径发出的信号促进了上述哮喘的每一种HASM特征。这项建议的主要目的是分析HASM中这一途径的炎症和遗传调节，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LILRB1、LilrB2及其家族成员LILRB4和SHP2(但不表达SHP1)均在人的ASM中表达；LILRB受体激活人气道肌细胞内的SHP2；SHP2增加收缩和弹力，刺激Akt信号和肥大，激活NF：B和趋化因子的形成。因此，人类白细胞抗原-G-LILRB-SHP2信号通路在HASM中是完整的，它的激活使哮喘样的表型传递给呼吸道肌肉。此外，人类白细胞抗原-G-LILRB-SHP2轴在哮喘中可能被异常地夸大，因为：哮喘患者BAL液中可溶性人类白细胞抗原-G的含量是正常志愿者的三倍；在哮喘呼吸道中发现的几种免疫调节分子可以增加LILRB的表达；并且这一途径的每个组成部分(编码SHP2的HLA-G、LILRB1、LilrB2、LILRB4和PTPN11)的基因变异与哮喘和/或支气管高反应性有关。综上所述，这些数据提示了一种新颖的生物学上可信的假说，即过度激活的HLA-G-LILRB-SHP2信号导致哮喘的HASM表型，干预这一信号通路的治疗干预可能会改善哮喘的ASM异常。为了验证这些假说，我们建议：1)确定选定的免疫调节分子如何影响正常和哮喘HASM中的HLA-G-LILRB-SHP2信号；2)评估与BHR或哮喘相关的LILRB1、LilrB2或LILRB4基因变异如何影响正常或哮喘HASM中的HLA-G-LILRB-SHP2信号；以及3)描述SHP2信号改变导致正常HASM获得哮喘HASM表型的分子机制。这些研究将揭示HLA-G-LILRB-SHP2信号如何调节ASM功能；哪些遗传和炎症机制调节这种调节作用；以及抑制这一途径是否可以阻止或逆转哮喘HASM表型的获得。(摘要结束)

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)