Key Points
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Inflammation is a beneficial process, designed to contain and eradicate threats to the host organism. Dysregulation of the magnitude or duration of inflammation contributes to multiple pathologies.
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Traditionally, drugs have been designed to reduce inflammation. Some such approaches — for example, non-steroidal anti-inflammatory drugs or pro-inflammatory cytokine ablation — achieve this by targeting factors that drive inflammation; others — for example, glucocorticoids — are directly anti-inflammatory.
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Active, specialized pathways bring about the resolution of inflammation. These involve discrete mediators and distinct cell phenotypes that act in a non-phlogistic manner to promote the clearance of inflammatory cells and a return to local tissue homeostasis.
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Recent advances in our understanding of the central processes in the resolution of inflammation — including pro-inflammatory mediator catabolism, dampening of downstream signalling, apoptosis and efferocytosis of inflammatory cells and their regulation — permit targeted pharmacological interventions to promote inflammatory resolution.
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The development of drugs that promote or mimic the mode of action of endogenous pro-resolution pathways may afford a novel complementary, or potentially superior, strategy to traditional options — thus regulating inflammation and restoring function, not merely suppressing inflammation.
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Recent discoveries suggest that the innate immune response, and in particular its resolution, may modulate the subsequent development of adaptive immunity and so may afford further therapeutic targets. Multiple challenges remain in developing human models of inflammatory resolution and in translating murine discoveries to date into drugs for humans.
Abstract
Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field.
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The authors wish to acknowledge the Wellcome Trust and the Medical Research Council for the financial support that has enabled the research that has contributed to this field.
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Glossary
- Eicosanoids
-
Twenty-carbon structures that are derived from arachidonic acid. Examples include the prostaglandins and the leukotrienes.
- Granulocytes
-
White blood cells that are characterized by granules in their cytoplasm. These include polymorphonuclear cells, eosinophils, basophils and mast cells.
- Efferocytosis
-
The removal of effete, mainly apoptotic, cells by professional phagocytes, especially macrophages.
- Zymosan
-
A ligand found on the surface of fungi. It binds to Toll-like receptor 2 (TLR2) and dectin receptors.
- Adenine- or uridine-rich elements
-
(AREs). 3′-untranslated regions of mRNA that recruit destabilizing factors and translational silencers.
- MicroRNAs
-
(miRNAs). Small non-coding RNA molecules, containing about 21–22 nucleotides, that function by base-pairing with complementary sequences within mRNA molecules.
- Exudates
-
Mixtures of cells and fluid that accumulate outside blood vessels during inflammation.
- Non-phlogistic
-
In a non-inflammatory manner.
- Co-inhibitory molecules
-
Molecules belonging to the immunoglobulin superfamily or the tumour necrosis factor receptor superfamily that inhibit T cell receptor- mediated responses.
- Polysensitization
-
A phenomenon in which sensitization to one allergen favours sensitization to other environmental allergens.
- Macrophage plasticity
-
The ability of macrophages to alter or adapt their biological function commensurate with the inflammatory environment they inhabit.
- Stress granules
-
Sites where untranslated mRNAs accumulate in cells that have been subjected to adverse environmental conditions.
- Acantholysis
-
Pathological separation of the epidermis from the dermis.
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Fullerton, J., Gilroy, D. Resolution of inflammation: a new therapeutic frontier. Nat Rev Drug Discov 15, 551–567 (2016). https://doi.org/10.1038/nrd.2016.39
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DOI: https://doi.org/10.1038/nrd.2016.39
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