Regulation of Neutrophil Function by Adenosine

Abstract

Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 . In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A 1 and A 3 adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A 2A and A 2B receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function.

Feedback Amplification of Neutrophil Function

“…receptors [57]. In addition, neutrophil-derived TNF-α has been shown to contribute to the amplification of IL-6 production by human neutrophils stimulated by a TLR8 ligand [58].…”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…As discussed above, the A 2B R is a G s -coupled protein receptor, which activates adenylyl cyclase and increases cAMP production; thus, this serves as a positive feedback mechanism wherein A 2B R increases its own expression and promotes renal fibrosis in the setting of hypoxia. Importantly, bone marrowderived cells involved in inflammation seen in early hypoxia co-express A 2A R and A 2B R; however, A 2A R has a much greater affinity for adenosine; thus, its effects likely predominate under physiologic conditions [57]. Under pathologic conditions, such as hyperglycemia and buildup of angiotensin II, local levels of adenosine increase and promote fibrosis by activation of A 2B R on mesangial cells and fibroblasts.…”

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“…Unlike the brief changes in tissue levels created by exogenously administered adenosine22 or adenosine‐receptor agonists,23 MSCs are capable of continuously and rapidly metabolizing ATP and AMP to adenosine by the actions of surface membrane ecto‐5′‐nucleotidases CD39 and CD73, respectively 24, 25, 26. Increased bioavailability of adenosine may subsequently favor an anti‐inflammatory microenvironment that mitigates the destructive potential of the innate immune response 24, 25, 26, 27. We found that implanted MSCs increase adenosine bioavailability through the action of CD73 and that this mechanism is critical to reducing early innate immune cell infiltration and ROS formation while protecting cardiac function following MI/R injury.…”