• The present review recapitulates relevant findings related to the role of the receptors of the innate immune system (TLRs and NLRs) in the progression of the most prevalent CVDs. • TLRs and NLRs play a key role in the progression of atherosclerosis, acute myocardial infarction or heart failure. • The development of new specific strategies to impair exacerbated TLR and NLR activation in CVDs are strong candidates for therapy and opens a new research field.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

In the aftermath of tissue injury or infection, an efficient resolution mechanism is crucial to allow tissue healing and preserve appropriate organ functioning. Pro-resolving bioactive lipids prevent uncontrolled inflammation and its consequences. Among these mediators, lipoxins were the first described and their pro-resolving actions have been mainly described in immune cells. They exert their actions mostly through formyl-peptide receptor 2 (ALX/FPR2 receptor), a G-protein-coupled receptor whose biological function is tremendously complex, primarily due to its capacity to mediate variable cellular responses. Moreover, lipoxins can also interact with alternative receptors like the cytoplasmic aryl hydrocarbon receptor, the cysteinyl-leukotrienes receptors or GPR32, triggering different intracellular signaling pathways. The available information about this complex response mediated by lipoxins is addressed in this review, going over the different mechanisms used by these molecules to stop the inflammatory reaction and avoid the development of dysregulated and chronic pathologies.

Myocarditis is an inflammation of the myocardium that can progress to a more severe phenotype of dilated cardiomyopathy (DCM). Three main harmful factors determine this progression: inflammation, cell death, and oxidative stress. Lipoxins and their derivatives are endogenous proresolving mediators that induce the resolution of the inflammatory process. This study aims to determine whether these mediators play a protective role in a murine model of experimental autoimmune myocarditis (EAM) by treating with the lipoxin A ₄ analog BML‐111. We observed that EAM mice presented extensive infiltration areas that correlated with higher levels of inflammatory and cardiac damage markers. Both parameters were significantly reduced in BML‐treated EAM mice. Consistently, cardiac dysfunction, hypertrophy, and emerging fibrosis detected in EAM mice was prevented by BML‐111 treatment. At the molecular level, we demonstrated that treatment with BML‐111 hampered apoptosis and oxidative stress induction by EAM. Moreover, both in vivo and in vitro studies revealed that these beneficial effects were mediated by activation of Nrf2 pathway through CaMKK2‐AMPKα kinase pathway. Altogether, our data indicate that treatment with the lipoxin derivative BML‐111 effectively alleviates EAM outcome and prevents cardiac dysfunction, thus, underscoring the therapeutic potential of lipoxins and their derivatives to treat myocarditis and other inflammatory cardiovascular diseases.

The role of extracellular nucleotides as modulators of inflammation and cell stress is well established. One of the main actions of these molecules is mediated by the activation of purinergic receptors (P2) of the plasma membrane. P2 receptors can be classified according to two different structural families: P2X ionotropic ion channel receptors, and P2Y metabotropic G protein-coupled receptors. During inflammation, damaged cells release nucleotides and purinergic signaling occurs along the temporal pattern of the synthesis of pro-inflammatory and pro-resolving mediators by myeloid and lymphoid cells. In macrophages under pro-inflammatory conditions, the expression and activity of cyclooxygenase 2 significantly increases and enhances the circulating levels of prostaglandin E₂ (PGE₂), which exerts its effects both through specific plasma membrane receptors (EP1-EP4) and by activation of intracellular targets. Here we review the mechanisms involved in the crosstalk between PGE₂ and P2Y receptors on macrophages, which is dependent on several isoforms of protein kinase C and protein kinase D1. Due to this crosstalk, a P2Y-dependent increase in calcium is blunted by PGE₂ whereas, under these conditions, macrophages exhibit reduced migratory capacity along with enhanced phagocytosis, which contributes to the modulation of the inflammatory response and tissue repair.

Background: SARS-CoV-2, the causative virus of the COVID-19 global pandemic, leads to a wide variety of responses among patients. Some of them present a very severe phenotype, while others only experience mild symptoms or are even asymptomatic. This differential prognosis is tightly related to the inflammatory status of the patient. Although WHO declared the end of the emergency, the pandemic caused a great socio-sanitary impact in all countries. Thus, the possible outbreak of new biological diseases in the future makes it necessary to deepen the knowledge of this uncontrolled immune response and look for reliable biomarkers to help us predict its potential health impact. Specialized pro-resolving lipid mediators (SPMs) as lipoxins are endogenous mediators synthesized from arachidonic acid in the resolution stage of any inflammatory process. These lipids have pro-resolving actions in several pathological models, including reducing NF-κB-mediated inflammation, and inducing the antioxidant response through the Nrf-2 pathway. Thus, although a potential relationship has already been suggested between low levels of SPMs and COVID-19 severity, their true role as a predictive biomarker is still unknown.Methods and results: In this study, we have analyzed by ELISA the serum levels of lipoxin A₄ (LXA₄) in a representative Spanish cohort. We found reduced levels in deceased patients when compared to mild or severe patients, concomitant with a decrease in the LXA₄ biosynthetic pathway and an increase in its degradation pathway. Furthermore, we have studied the correlation between the levels of this SPM and several pathology indicators, finding a significant correlation between increased LXA₄ levels and a better prognosis of the patients.Conclusion: We propose to measure systemic LXA₄ as a new promising biomarker to predict the survival in patients affected by SARS-CoV-2 and presumably to other viruses that can affect humanity in the future.