Specialized pro-resolving mediator network: an update on production and actions

Abstract

Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2–3 years from human and preclinical animal studies, together with the structural–functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.

Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial

“…Mediators of the resolution phase skew the immune response to clearance mechanisms of apoptotic cells, debris and microbes while limiting inflammatory activation ( Serhan, 2014 ). This process actively promotes healing and repair and drives a tissue back to homeostasis after an acute infection and/or injury ( Chiang and Serhan, 2020 ).…”

“…Polyunsaturated fatty acids (PUFA) serve as the substrate for pro-inflammatory, anti-inflammatory, and specialized pro-resolving lipid mediators (SPM) ( Chiang and Serhan, 2020 ). Specifically, the omega-6 PUFA arachidonic acid (AA) is substrate for the lipoxygenase and cyclooxygenase pathways, which generate leukotrienes and prostaglandins, respectively, collectively referred to as eicosanoids ( Figure 1 ).…”

The need for precision nutrition, genetic variation and resolution in Covid-19 patients

“…These are the cellular signs of resolution governed by the n-3 PUFA chemical mediator superfamily comprised of the resolvin, protectin and maresin families that together are collectively coined specialized proresolving mediators or SPM. Their precise individual stereochemistry is critical in stimulating cellular functions via specific cell surface receptors [ 20 , 21 ] that stimulate resolution and protect organs ( Figure 2 ). This precise stereochemistry of the SPMs arises from the chemistry inherited from their n-3 PUFA precursors present in our diets.…”

“…This precise stereochemistry of the SPMs arises from the chemistry inherited from their n-3 PUFA precursors present in our diets. The SPMs each counter-regulate cytokine storms as well as proinflammatory lipid mediators via NFkB and inflammasome down-regulation [ 20 , 21 ] and unlike anti-inflammatory agents that eventually become immunosuppressive, SPMs control both the killing and clearance of microbes.

Figure 2 Pro-Resolving Mediators Network: Biosynthesis, Receptors and Functions.

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“…In SARS-CoV-2 activated human macrophages, Resolvin D1 and Resolvin D2 each dramatically reduce the cytokine storm diminishing the levels of key pro-inflammatory cytokines including TNF-α, IL-8 and MIP-1 [ 22 ]. SPMs also reduce eicosanoids [ 19 ] that amplify and are mediators of inflammation, namely prostaglandins and leukotrienes from ARA [ 20 , 21 ] that are each present in peripheral blood of Covid-19 patients along with resolvins that dynamically change with disease severity [ 23 ]. The lung is a major organ where cytokine and eicosanoid storms contribute to the Covid-19 host evoked response that increases the likelihood of a poor outcome for many of these patients.…”