ReviewAspirin and immune system
Highlights
► ASA and immune cells. ► Clinical prospects of ASA with respect to the immunopathologic response in autoimmunity. ► Clinical prospects of ASA with respect to the immunopathologic response in allograft rejection, and immunotolerance.
Introduction
Acetylsalicylic acid (ASA) or aspirin represents the prototype of non-steroidal anti-inflammatory drugs. Initially, after its innovative follow up from salicylic acid by Felix Hoffman (1897), ASA had been reported as the world's first truly synthetic drug possessing anti-inflammatory activity against rheumatism. At present, ASA has achieved clinical prominence as a globally relied therapeutic agent not only because of its traditional anti-inflammatory paradigm, but also for its more advanced life-saving perspective related to cardiovascular events (heart attacks, stroke, etc.) [1]. Moreover, the nitric oxide (NO) derivatives of ASA (the NO-aspirins such as NCX-4016, NCX-4040, etc.) are also acquiring clinical approval because of their gastroprotective peculiarity as compared to ASA [[2], [3], [4]]. Pharmacologically, ASA exerts its anti-inflammatory effects through its typical cyclooxygenase (COX) inhibitory mechanism of action [5], [6]. However, it has now been definitely explored that ASA also exerts variety of its anti-inflammatory actions via biosynthesis of proresolution 15R-epilipoxin A4, the so-called aspirin-triggered lipoxins (ATLs) [7], [8]. In addition, clearly evident data suggests that ASA also have some COX-independent mechanisms, including induction of NO release [9], enhancement of adenosine production by increasing adenosine triphosphate hydrolysis [10], [11], and the inhibition of nuclear factor-kappa B (NF-kB) transcriptional pathway [12].
As an extension of its pharmacological actions, ASA also exhibits the immunopharmacological properties. This is noteworthy that interest in the immunoregulatory ability of ASA has exploded in the last three or four decades and a number of studies have outlined its apparent immunomodulating role. In this review, we will discuss the ASA-mediated immune regulation focusing on its effects on different immune cells, including neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, T effector cells, T regulatory (Treg) cells, and B cells. In addition, we will also highlight the clinical prospective of ASA in terms of autoimmunity, allograft rejection and immunotolerance.
Section snippets
Inflammation, prostanoids and the immune system
In general, the principal role of the immune system is to protect the host from the invading pathogenic assailants (microbial or non-microbial). The concept of self-tolerance describes that, despite all of the discretionary aptitude to contend against infectious or non-infectious foreign agents, the immune system does not induce rejection against self-antigens [13], [14]. Notwithstanding, the collapse of self-tolerance can trigger an immunologic culprit attack against self-antigens and may lead
ASA and neutrophils
Neutrophils are the key players of innate immunity. After extravasation (adhesion, transmigration, chemotaxis, etc.) from circulatory system toward the site of infection or tissue damage, they produce a variety of inflammatory cytokines and chemokines through the involvement of NF-kB and mitogen-activated protein kinase (MAPK) pathways [34].
ASA can suppress the neutrophil-mediated innate immune responses by decreasing their extravasation, a distinctive step in the innate immunity (Fig. 1).
Clinical prospects of ASA with respect to the immunopathologic response in autoimmunity, allograft rejection, and immunotolerance
The last several years of immunology-based scrutinies of ASA have produced a great interest in, and the data about, its immunotherapeutic implication against the immunopathologic responses. In autoimmunity, ASA has a long-lasting remedial respect for rheumatoid arthritis, although the majority of contributing data has been addressed primarily by population studies. Experimentally, ASA was reported to inhibit the anti-type II collagen antibody formation not only in type II collagen-induced
ASA and the immune-hypothalamic–pituitary–adrenal axis
The bidirectional communication between the immune and neuroendocrine systems can activate the hypothalamic–pituitary–adrenal (HPA) axis that plays a key role in subserving the body's response to different stimuli including stress (physical or psychological) and the inflammatory mediators (such as cytokines and PGs), thereby maintaining the homeostatic balance via the neuroendocrine hormonal release (e.g. adrenal glucocorticoids) [[147], [148], [149]]. Compelling data emerging from prior
Concluding remarks and future dimensions
This review clearly describes the immunomodulatory potential of ASA and its derivatives. ASA exerts multiple effects on different components of innate and adaptive immunities. It can induce apoptosis in different immune cells, modulate their proliferation/maturation process, regulate their cytokine production, and can also trigger a lipoxin-driven immune counter-regulation. Together with this, the immunosuppressive capability of ASA through induction of tolerogenic DCs and then subsequent
Conflict of interest
The authors confirm that there are no conflicts of interest.
Acknowledgments
We thank the many researchers who have contributed to our current understanding of ASA and its derivatives.
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These authors equally contributed to this work.