It is relevant to consider the inflammatory reaction as a biphasic process, with an initial phase of induction and a second phase of resolution. During the initial phase of inflammation, eicosanoids including prostaglandins and leukotrienes play an important role as local mediators in the development of an inflammatory condition, evoking potent chemotactic responses from leukocytes, the activation of which is coupled to the production of pro-inflammatory cytokines at sites of inflammation [107]. The second stage of resolution is coupled to the biosynthesis of a new genus of lipid mediators that actively limit inflammation and promote resolution. This new genus of pro-resolving mediators includes lipoxins (LXs) and their aspirin-triggered carbon-15 epimers, as well as the recently discovered resolvins and protectins, which are derived from omega-3 fatty acids. An excellent review [108] on these new mediators has been published recently, and we give a summary below of the main principles described in this review.

LXs and aspirin-triggered LXs (ATLs) are considered to act as 'braking signals' in inflammation, dampening the inflammatory response. Aspirin triggers the generation of epimeric forms of LXs. Cells that express COX-2 (including activated monocytes, macrophages, and microglia) produce ATLs in response to the actions of aspirin, which triggers the endogenous formation of carbon-15 epimeric LXs. In particular, in a cytokine-primed milieu, acetylation of COX-2 by aspirin switches the catalytic activity of the enzyme to an R-lipoxygenase with the formation of 15R-hydroxyeicosatetraenoic acid, which is rapidly converted by 5-lipoxygenase to 15-epimeric-LXA4 or 15-epimeric-LXB4.

Administration of low doses of aspirin to healthy subjects significantly increases plasma levels of ATLs, with concomitant inhibition of thromboxane biosynthesis, suggesting that ATLs may account for some of the beneficial effects of aspirin that are not strictly related to its anti-thrombotic actions.

The role for ATLs as anti-inflammatory molecules is well defined, with their bioactions involving the inhibition of neutrophil and eosinophil recruitment and activation. In addition, LXs and ATLs have been proposed to directly stimulate expression of genes (such as NAB1) involved in endogenous anti-inflammation and resolution, and to regulate NF-κB activation.

The actions of LXs and ATL are not limited to counter-regulating the evolution of inflammation, as they also promote resolution at different levels. LXs stimulate monocyte chemotaxis and adherence, without causing degranulation or release of ROS, suggesting that the actions of LXs are related to the recruitment of monocytes to sites of injury. These monocyte activities may be host-protective. in view of the important role of these cells in wound healing and resolution at inflammatory sites. Indeed, LXs and ATLs stimulate the in vitro clearance of apoptotic cells by human monocyte-derived macrophages in a non-phlogistic manner. In addition to promoting resolution by non-phlogistic phagocytosis of apoptotic cells, LX can act to reprogram cytokine-primed macrophages from a classic pro-inflammatory phenotype to an alternatively activated phenotype.

A range of doses of aspirin (100 to 300 mg/day) reduced the plasma levels of inflammatory biomarkers such as CRP, IL-6 and TNF-α in patients with cardiovascular metabolic syndrome [109]. Aspirin was shown to reduce the levels of inflammatory cytokines, such as TNF-α and IL-8, but not those of negative immunoregulatory cytokines, such as IL-4 and IL-10 [110]. In the same study, there did not seem to be any effect of aspirin on IL-1β, and the suppressant effects of aspirin on IL-6 did not reach significance. Aspirin also reduced the production of TNF-α in rats with streptozotocin-induced type 2 diabetes [111]. Pretreatment with aspirin in various cell types, including keloid fibroblasts and HeLa cells, significantly reduced IL-1 and TNF-α-induced stimulation of nuclear factor (NF-)-κB [112, 113]. In patients with chronic stable angina, treatment with aspirin for 6 weeks reduced serum levels of CRP and IL-6 [114]. Another study examined the effects of 2 weeks of treatment with oral aspirin (325 mg/day) on the ex vivo stimulated production of IL-1β, IL-6, and TNF-α by peripheral blood mononuclear cells from normal controls [115]. The authors found that oral aspirin may increase the production of cytokine-induced, but not lipopolysaccharide (LPS)-induced TNF-α and IL-1β production, suggesting that short-term treatment with aspirin might augment cytokine-induced cytokine production in normal controls. Taken together, these results provide some evidence that administration of aspirin to patients with inflammatory conditions may suppress the production of TNF-α, IL-1β and maybe IL-6, and of acute-phase proteins such as CRP. Aspirin also seemed to reduce Th17 responses in mouse models of LPS-induced lung inflammation [116].

There is also evidence that mRNA expression of COX-2 is increased in individuals with recurrent depression [117]. Likewise, a significant association was found between recurrent depression and a single-nucleotide polymorphism of the COX gene G-765C [118]. Nevertheless, as discussed above, these findings question the use of selective COX-2 inhibitors in clinical depression [102]. COX-2 has many effects, both negative and positive, on the central nervous system, meaning that the outcome of COX-2 inhibition in neuroinflammation is very difficult to predict [119]. For example, COX-2 has neuroprotective and anti-inflammatory effects, and may play a role in the integrity of the blood-brain barrier, synaptic transmission, and long-term potentiation [102, 119–121]. These new data augment the view that COX-2 may not be the best target to inhibit neuroinflammation, and therefore targeting COX-1 could be a much better strategy to block neuroinflammation [119, 120]. There are now data indicating that expression of COX-1 is enhanced in neuroinflammatory disorders, including models of PD, and that COX-1 inhibition improves survival [122]. Taken together, these new data show that COX-1, rather than COX-2, is a key component in neurodegeneration and neuroinflammation [123]. Thus, the working spectrum of aspirin (targeting preferentially COX-1 rather than COX-2) compared with that of selective COX-2 inhibitors may be the reason why aspirin is an asset in the treatment of neuropsychiatric conditions associated with neuroinflammation and neuroprogression.

It is thus tempting to speculate that aspirin is capable of deactivating and reprogramming the activated monocytes, macrophages, and T cells and the neuroinflammatory responses in neuropsychiatric disorders.