Regulation of the A2a receptor by extracellular matrix fragments

描述(申请人提供)：组织微环境在调节炎症中起着关键作用。细胞外基质(ECM)分解产物不仅是炎症的副产物，而且在控制炎症的持续时间和强度方面起着至关重要的作用。当ECM在炎症过程中降解时，会产生低分子透明质酸(LMW HA)碎片，通常在愈合过程中会被清除。然而，在持续的炎症过程中，有持续的组织破坏和组织微环境中低分子HA片段的持续存在。除低分子透明质酸外，炎症后的组织微环境中还存在腺苷。腺苷作为炎症和组织破坏的负性调节因子，特别是通过腺苷A2a受体(A2aR)的参与。我们认为，降解的透明质酸以低分子量透明质酸片段的形式，通过下调A2aR的表达，从而阻止其抗炎作用，在调节免疫反应的大小和质量方面发挥重要作用。因此，炎症的结局取决于促炎症的LMW HA和抗炎的A2a受体之间的相互作用。对ECM增强炎症能力的潜在途径的了解可能会导致潜在的药物干预靶点。我们相信，我们的研究将确定一种新的机制，通过LMW HA下调抗炎A2aR，从而促进炎症导致组织纤维化。

DESCRIPTION (provided by applicant): The tissue microenvironment plays a critical role in regulating inflammation. Extracellular matrix (ECM) breakdown products are not only a byproduct of inflammation but play an essential role in controlling the duration and intensity of the inflammation. As the ECM is degraded during inflammation, low molecular weight hyaluronan (LMW HA) fragments are generated that are normally cleared during the healing process. However, during continual inflammation there is ongoing tissue destruction and persistence of LMW HA fragments in the tissue microenvironment. In addition to LMW HA, adenosine is present in the tissue microenvironment following inflammation. Adenosine acts as a negative regulator of inflammation and tissue destruction specifically thorough adenosine A2a receptor (A2aR) engagement. We propose degraded hyaluronan, in the form of LMW HA fragments, plays an important role in modulating the magnitude and quality of an immune response by down-regulating the expression of the A2aR thereby preventing its anti-inflammatory effects. Thus, the outcome of inflammation is determined by the interplay between pro-inflammatory LMW HA and the anti-inflammatory A2a receptor. An understanding of the pathways underlying the ability of ECM to augment inflammation may lead to potential targets for pharmacologic intervention. We believe that our studies will identify a novel mechanism by which LMW HA down regulates the anti-inflammatory A2aR thus promoting inflammation leading to tissue fibrosis.