Immunological alterations mediated by adenosine during host-microbial interactions

Abstract

Adenosine accumulates in inflammation and ischemia but it is more than an end-product of ATP catabolism. Signaling through different receptors with distinct, cell-specific cytoplasmic pathways, adenosine is now recognized as an inducible switch that regulates the immune system. By acting through the A(2A)AR, adenosine shapes T cell function, largely by conferring an anti-inflammatory tone on effector Th cells (Teff) and natural killer (NK)T cells. In contrast, both the A(2A)AR and A(2B)AR are expressed by antigen-presenting cells (APC) which have been shown to regulate innate responses and the transition to adaptive immunity. There is also emerging evidence that adenosine production is one mechanism that allows some pathogens as well as neoplasms to evade host defenses. This review discusses the immunoregulatory functions of adenosine and some of the interactions it may have in regulating host-microbial interactions.

Fig. 1

Adenosine synthesis and control of host responses to limit tissue damage. ATP can accumulate in areas of inflammation or hypoxia from dead cells or bacteria [2]. The metabolism of ATP can be achieved by CD39 and CD73 leading to the accumulation of adenosine (ADO). These enzymes are expressed differentially by various cells but both are found on Treg and contribute to their regulatory function. Subsequently, the adenosine can interact with any of the four receptor subtypes, primarily the A_2A and A_2BAR but possibly A1AR and A3AR as well. The short half-life of adenosine requires a close juxtaposition among cells producing and responding to its signals suggesting its effects are largely paracrine or autocrine. This figure is modified from [26]

Fig. 2

Control of host responses by adenosine-producing bacteria. As the immunological functions include the impairment of host responses, one might predict that microbes have developed ways to synthesize adenosine and favor their colonization. Indeed, Gram-positive bacteria express an extracellular 5′-nucleotidase, AdsA, that converts 5′AMP to adenosine (ADO) in a manner similar to CD73. Subsequently, local immune/inflammatory cells are inhibited and this local immune suppression favors the expansion and colonization of the organism