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

Abstract

Collagen and matrix deposition by fibroblasts is an essential part of wound healing but also contributes to pathologic remodeling of organs leading to substantial morbidity and mortality. Adenosine, a small molecule generated extracellularly from adenine nucleotides as a result of direct stimulation, hypoxia, or injury, acts via a family of classical sevenpass G protein-coupled protein receptors, A 2A and A 2B , leading to generation of cAMP and activation of downstream targets such as PKA and Epac. These effectors, in turn, lead to fibroblast activation and collagen synthesis. The regulatory actions of these receptors likely involve multiple interconnected pathways, and one of the more interesting aspects of this regulation is opposing effects at different levels of cAMP generated. Additionally, adenosine signaling contributes to fibrosis in organ-specific ways and may have opposite effects in different organs. The development of drugs that selectively target these receptors and their signaling pathways will disrupt the pathogenesis of fibrosis and slow or arrest the progression of the important diseases they underlie.

Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs

“…Earlier reports revealed a critical role of ADORA2A signaling in dermal fibrosis induced, for example, by genetic loss of adenosine deaminase, systemic administration of bleomycin, and ionizing radiation, whereas ADORA2B activation was shown to play a major pathogenic role in the related models of pulmonary fibrosis (35, 51, 67, 68). These differences might be due to tissue‐specific expression patterns of adenosine receptors or other fibrosis‐modulating signaling molecules in resident cells or recruited immune cells, tissue‐specific damage responses, or both (67, 68). However, the models of radiation‐induced fibrosis in the lung and the skin also differ in the radiation dose (15 Gy in the lung vs. 35–40 Gy in the skin) and the time course (weeks vs. months).…”

Adenosine A 2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis

“…Indeed, it is likely that many of the effects of A2AR stimulation on new bone formation, as seen in vivo in these studies, are mediated through the WNT/b-catenin signaling pathway. In fibroblasts, the A2AR most likely mediates its effects on WNT signaling via activation of exchange protein directly activated by cAMP 1/2 (EPAC1/2) and downstream activation of p38MAPK and PKB (AKT) (36,49,50). The precise signaling interactions and the downstream signaling elements involved in EPAC1/2 signaling for osteoclast differentiation are not completely understood, although they are likely to involve regulation of cytoskeletal assembly, the effects for which EPAC1/2 signaling is best understood (48).…”

Adenosine A2A receptor promotes collagen type III synthesis via β‐catenin activation in human dermal fibroblasts

“…Adenosine, by acting on A 2A and A 2B receptors, increases both Col1 and Col3 synthesis in vitro and in animal models (Perez‐Aso et al, , ). Adenosine receptors are differentially expressed in different tissues and signal via distinct pathways downstream from the secondary messenger cAMP (Shaikh and Cronstein, ). For example, the A 2B receptor mediates renal fibrosis in the setting of hypoxia by inducing the expression of endothelin‐1 (Sorokin and Kohan, ; Kong et al, ).…”

“…However, the wound healing process can be diverted or become overly active leading to excessive matrix production. Dermal fibrosis, which is the pathological remodelling of skin characterized by the excessive accumulation of collagen and other matrix elements, underlies a wide range of clinically important diseases including hypertrophic scarring, keloid and morphea (Andrews et al, ; Shaikh and Cronstein, ). Scleroderma and other diffuse fibrosing conditions, although uncommon, cause multiple morbidities in affected people, including disfigurement and a diminished range of movements as well as premature mortality as a result of renal and cardiac dysfunctions (Balbir‐Gurman and Braun‐Moscovici, ).…”