Plasma glutamate–modulated interaction of A(2A)R and mGluR5 on BMDCs aggravates traumatic brain injury–induced acute lung injury

The bone marrow–derived cell (BMDC)–associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A(2A) receptor (A(2A)R) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A(2A)R exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid–induced ALI model (a nonneurogenic ALI model.) Moreover, the A(2A)R agonist CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A(2A)R and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C–protein kinase C signaling, which mediated the proinflammatory effect of A(2A)R. These results are in striking contrast to the well-known antiinflammatory and protective role of A(2A)R in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A(2A)R.