Adenosine Acts Through A2AR to Alleviate the Inflammatory Response Caused by Activation of Perivascular-Resident Macrophage-Like Melanocytes

Disruption of the blood labyrinth barrier (BLB) is considered a pathological cause of diverse hearing impairments. Perivascular-resident macrophage-like melanocytes (PVM/Ms) play a critical role in maintaining inner ear homeostasis and BLB integrity. Activation of PVM/Ms leads to decreased production of pigment epithelium-derived factor (PEDF), contributing to BLB breakdown. This study investigated the role of the adenosine A2A receptor (A2AR) pathway in lipopolysaccharide (LPS)-induced inflammation in PVM/Ms and elucidated the underlying mechanisms.

The anti-inflammatory effects of adenosine and its specific receptor A2AR were evaluated in LPS-induced PVM/Ms. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) were measured by quantitative real-time PCR (qRT-PCR) and enzyme linked immunosorbent assay (ELISA). Additionally, matrix metalloproteinase-9 (MMP-9) and PEDF were quantified using western blot and ELISA, respectively. An endothelial cell (EC)-PVM/M co-culture model exposed to LPS was established and treated with adenosine and SCH58261 to assess effects on BLB permeability.

LPS treatment significantly changed the production of inflammatory factors, including IL-6 and TNF-α, as well as MMP-9, TIMP-1, and PEDF. These changes were abrogated by adenosine, which also reduced the production of reactive oxygen species (ROS) and inhibited the activation of PVM/Ms. SCH58261 partially reversed the effects of adenosine following LPS treatment. The p38 MAPK pathway was found to be involved in adenosine regulation of LPS-induced PVM/Ms.

Adenosine attenuates the inflammatory activation of PVM/Ms and enhances their ability to maintain endothelial barrier integrity by binding to A2AR. The findings support adenosine and A2AR as potential therapeutic targets for treating hearing impairments.