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Resolving inflammation

Review

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediatorsCharles N. Serhan,* Nan Chiang,* and Thomas E. Van Dyke# Author information Copyright and License information

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents newly uncovered cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and new families of endogenous chemical mediators, termed resolvins and protectins. These mediators carry antiinflammatory and pro-resolution properties with leukocytes, protect organs and stimulate mucosal antimicrobial defence and clearance. Together, they control local inflammatory responses at multiple levels to stimulate resolution.

Introduction

On challenge of host tissues by microorganisms, tissue injury or surgical trauma, two main routes lead to release of exogenous and endogenous chemical mediators that in turn give rise to the initial cardinal signs of inflammation described by Celsus in the first century1, rubor (redness), calor (heat), tumor (swelling) and dolor (pain) (FIG. 1). Exogenous mediators include microbial-derived peptides that are chemoattractants and recruit neutrophils to the site, where they can phagocytoze microbial invaders and cellular debris. Within neutrophils, newly formed phagosomes fuse with lysosomal granules to become phagolysosomes. These granules contain degradative enzymes and produce reactive oxygen species (ROS) to kill trapped microorganisms or degrade cellular debris. Hence the initial inflammatory response is host protective and its timely resolution ideally self-limited.

Figure 1

Decision paths in acute inflammation: resolution or chronic inflammation and the roles of endogenous chemical mediators

Decision paths in acute inflammation: resolution or chronic inflammation and the roles of endogenous chemical mediators

Sometimes neutrophil granule contents can inadvertently spill into the extracellular milieu before complete engulfment of microorganisms or debris2. This leads to local tissue damage and amplification of acute inflammatory signs within minutes to hours of insult (FIG. 1). This unintentional spilling of granule contents, in particular the release of hydrolytic enzymes from phagolysosomal vacuoles also occurs when phagocytes encounter foreign surfaces that they attempt to ingest but cannot, such as crystals, bacterial biofilms or other slimy surfaces1.

The intentional generation of endogenous chemical mediators, including eicosanoids (i.e. prostaglandin E2, leukotriene B4) and complement components (C5a), and their local release from infiltrating cells, which are physiologic events during host defence, can also lead inadvertently to tissue damage. Endogenous chemical mediators are released during sterile injury as in ischemia-reperfusion injury. This route of chemical mediator release can be amplified by overt activation and excessive recruitment of neutrophils to the site of injury that in turn aggravates further spilling of noxious granule-contents as well as generation of new mediators at the site, which sustains the cardinal signs of inflammation (FIG. 1).

Acute inflammation has several programmed fates including progression to chronic tissue fibrosis or the ideal outcome of complete resolution. Challenges are met by infiltrating phagocytic cells of the innate system, primarily neutrophils, that traffic sensing gradients of chemoattractants from postcapillary venules via diapedesis (FIG. 1). These chemoattractants consist of endogenous lipid mediators, such as leukotrienes, and protein mediators, including chemokines and cytokines, as well as exogenous chemoattractants liberated, for example, from microorganisms. Time-dependent progression of cell infiltration is led by specific leukocyte subtypes, namely, professional phagocytes, neutrophils being the first to enter, followed by monocytes.

Once initiating noxious materials are removed via phagocytosis, the inflammatory reaction must be resolved to prevent the inflammation from spreading, becoming chronic or causing disease. Resolution of inflammation, or its catabasis6, is the reduction or removal of leukocytes and debris from inflamed sites enabling the return to homeostasis. The resolution of inflammatory leukocytic infiltrates was previously considered to be passive. Local chemotactic stimuli and gradients, for example, were thought to dissipate or simply “burn out” with time, enabling tissues to drain, repair and return to normal function1. With recent findings reviewed here, it is now apparent that resolution is not merely a passive termination of inflammation, but rather an active biochemical and metabolic process. The resolution process is rapidly initiated after acute challenges by cellular pathways that actively biosynthesize local specialized dual-acting anti-inflammatory and pro-resolution lipid mediators, such as lipoxins, resolvins and protectins(Fig1).

Concluding remarks and future directions

With the discovery of lipid mediators that possess both anti-inflammatory and pro-resolution activities (dual action mediators), these new families of resolvins and protectins and class of eicosanoids, e.g., lipoxins, constitute a novel genus of pro-resolution mediators. Together, they help open new avenues for treatment and the potential for resolution-based pharmacology and lipidomics-based therapeutics. Since many current and widely used drugs were developed without knowledge of their impact in resolution circuits, some agents, such as selective COX2 inhibitors and certain lipoxygenase inhibitors, have proven to be toxic to the tissue programmes of resolution, delaying the return to homeostasis, whereas others, such as glucocorticoids, aspirin, cyclin-dependent kinase inhibitors and statins, seem to work in concert with endogenous pro-resolution processes. Hence, in the near future resolution-directed therapeutics may involve small molecule mimetics in designer resolution-anti-inflammatories. COX inhibitors reduce the amplitude of and cardinal signs of inflammation by inhibiting prostanoid biosynthesis. Thus, combining pro-resolution molecules together with LOX or COX pathway antagonists may be a useful strategy to rescue resolution and control excessive inflammation. Also, pro-resolution mediators may have therapeutic potential in settings where sustained inflammation and impaired resolution are components of disease pathophysiology.

The relationship between essential fatty acids in nutrition, dietary supplementation and the biosynthesis of resolvins and protectins is an area of active interest. Along these lines, our studies with Kang and colleagues in fat-1 transgenic mice, which overexpress fatty acid desaturase from C. elegans, help to address discrepancies in dietary studies that can arise from individual genetic and feeding variations. The fat-1-transgenic mice produce and store higher levels of EPA and DHA in their tissues and as a result generate increased levels of resolvins and protectins. On provocation, fat-1-transgenic mice show reduced gastrointestinal inflammation and less tumor metastasis. Whether these exciting findings extend to humans will be of interest in further studies.

Lipoxins and resolvins act at multiple tissue and cellular levels with different receptors. Susceptibility to chronic inflammatory disorders may therefore result from uncontrolled resolution circuits that can arise from defects in either receptors and/or their signalling, or in de novo biosynthesis of pro-resolution molecules. In the case of periodontal disease, which has many of the pathogenic features, including infection, observed in chronic inflammatory disorders in other locations in the body, the stage is now set for proof of principle in humans, because lipoxin A4 and resolvin E1 both reduce inflammation in periodontal disease in rabbits and mice and expedite the return to homeostasis.

It is worth pointing out that resolvins and protectins are structures that are conserved in evolution, as they are present in fish brain and haematopoietic tissues. It will be important to learn whether resolution pharmacology leads to new treatments for human disease. For example, will it be possible to treat organ specific inflammatory disorders with different pro-resolution mediators and/or their analog mimetics, with tissue specific precision? Will dietary supplementation with intermediates and/or precursors be beneficial for the local production of pro-resolution mediators? Will knowledge of these new pathways lead to an increased appreciation of potential deleterious effects of excess DHA and EPA intake that could lead to increases in autooxidation of these fatty acids that can damage cells and tissues initiating inflammation? It is likely that the serum levels of EPA and DHA are tightly regulated and that exceeding their physiological boundaries could have a negative impact in human systems. Moreover, since lipoxins, resolvin E1 and protectins act on T cells, dendritic cells and phagocytic cells, communication(s) between the innate and cellular immune systems appears likely to have a molecular link to nutrition. Further evidence is needed to substantiate these points. In relation to essential fatty acids, knowledge of these temporal-spatial signalling pathways and their actions should be harnessed in humans to improve health and reduce disease.

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