Scientific Background
Autoimmune diseases are chronic conditions initiated by the loss of
immunological tolerance to self-antigens, leading to self-attack of the
immune system on one’s organs. Although differing from each other,
autoimmune diseases present several shared common phenotypes: the
presence of nonspecific autoantibodies [i.e., antinuclear antibodies
and double-strand DNA (dsDNA)], high levels of cytokines, and the
presence of infiltrating immune cells. Anti-dsDNA is a known hallmark of
lupus and other autoimmune diseases, but it is not only a disease
marker, it also promotes autoimmunity. The presence of dsDNA in the
cytoplasm has been described as a potent danger signal that activates
stimulator of interferon genes (STING), a regulator of the immune
response (1). Activating STING leads to a signaling cascade that
eventually alters pro-inflammatory molecule production. A defect or
unnecessary alert in this mechanism has been described as underpinning
the auto-inflammatory process (2). One source of dsDNA is related to the
production of neutrophil extracellular traps (NETs). Activated
neutrophils extrude their DNA and bactericidal molecules, creating NETs
in a unique type of cell death called NETosis (3). Neutrophils from
patients with various autoimmune diseases are more likely to undergo
NETosis than those of healthy donors (4). Moreover, the presence of
autoantibodies promotes the release of NETs.
Adenosine is a potent modulator of lymphocyte development,
proliferation, and activity (5-7). There are four types of adenosine
receptors, all of which are members of the G protein-coupled receptor
family: A1, A2A, A2B,
and A3. The A1 (A1R) and
A3 receptors (A3R) activate Gi, which
inhibits adenylyl cyclase activity and decreases cAMP levels and promote
pro-inflammatory response. A2A receptor
(A2AR) interacts with Gs, and the A2Breceptor (A2BR) interacts with Gs/Gq to induce adenylyl
cyclase activity and elevates cAMP levels, thus, promoting
anti-inflammatory responses (3). A1R exerts the highest
affinity for adenosine, and it is the first to react in the early phase
of inflammation, while Gs-coupled A2AR is related to
immunosuppression and resolution of inflammation.
Adenosine receptors expressed on a wide variety of both non-immune and
immune cells (8) and all four adenosine receptors have been described on
neutrophils (9). A1R stimulation enhances their
adherence to endothelium, chemotaxis (8), and their activity (10), while
A2AR inhibits neutrophil trafficking and effector
functions such as oxidative burst, inflammatory mediator production, and
granule release (reviewed in (11, 12)). Multiple reports suggest that
the onset of autoimmune disorders is at least in part related to a
partial or complete loss of function in the purinergic pathways and to
local defective production of adenosine (reviewed in (9)).
In a model of SIRS, we have previously shown that a surge of adenosine
desensitizes Gi-coupled adenosine A1R
and upregulates Gs-coupled A2AR, an
effect that provokes a cAMP-dependent lymphotoxic response. The
depletion of lymphocytes and their functional impairment has been
thought to be part of the pathology in SIRS that worsens recovery and
decreases chances of survival (13). We now suggest that
adenosine-dependent lymphocyte depletion observed in SIRS might be a
normal physiological mechanism that minimizes lymphocyte exposure to
self-antigens to reduce the prevalence of autoimmunity.
In the current study, we aimed to evaluate the protective role
A1R and A2AR have in the prevention of
autoimmune diseases.