The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion.
Endogenous mediators within the inflammatory milieu play a critical role in directing the scope, duration, and resolution of inflammation. High-molecular-weight extracellular matrix hyaluronan (HA) helps to maintain homeostasis. During inflammation, hyaluronan is broken down into fragments that induce chemokines and cytokines, thereby augmenting the inflammatory response. Tissue-derived adenosine, released during inflammation, inhibits inflammation via the anti-inflammatory A2 adenosine receptor (A2aR). We demonstrate that adenosine modulates HA-induced gene expression via the A2aR. A2aR stimulation inhibits HA fragment-induced pro-fibrotic genes TNF-alpha, keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-2, and MIP-1alpha while simultaneously synergizing with hyaluronan fragments to up-regulate the TH1 cytokine IL-12. Interestingly, A2aR stimulation mediates these affects via the novel cAMP-activated guanine nucleotide exchange factor EPAC. In addition, A2aR-null mice are more susceptible to bleomycin-induced lung injury, consistent with a role for endogenous adenosine in inhibiting the inflammation that may lead to fibrosis. Indeed, the bleomycin treated A2aR-null mice demonstrate increased lung inflammation, HA accumulation, and histologic damage. Overall, our data elucidate the opposing roles of tissue-derived HA fragments and adenosine in regulating noninfectious lung inflammation and support the pursuit of A2aR agonists as a means of pharmacologically inhibiting inflammation that may lead to fibrosis.
Scheibner
Kara A
KA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Boodoo
Sada
S
Collins
Samuel
S
Black
Katharine E
KE
Chan-Li
Yee
Y
Zarek
Paul
P
Powell
Jonathan D
JD
Horton
Maureen R
MR
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D018664:Interleukin-12; D006820:Hyaluronic Acid; D000241:Adenosine