Review
Aspirin and immune system

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Abstract

The time-tested gradual exploration of aspirin's diverse pharmacological properties has made it the most reliable therapeutic agent worldwide. In addition to its well-argued anti-inflammatory effects, many new and exciting data have emerged regarding the role of aspirin in cells of the immune system and certain immunopathological states. For instance, aspirin induces tolerogenic activity in dendritic cells and determines the fate of naive T cells to regulatory phenotypes, which suggests its immunoregulatory potential in relevance to immune tolerance. It also displays some intriguing traits to modulate the innate and adaptive immune responses. In this article, the immunomodulatory relation of aspirin to different immune cells, such as neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, and the T and B lymphocytes has been highlighted. Moreover, the clinical prospects of aspirin in terms of autoimmunity, allograft rejection and immune tolerance have also been outlined.

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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