FASEB J. Author manuscript; available in PMC 2011 Jun 21. Published in final edited form as: FASEB J. 2007 Feb; 21(2): 325–332. doi: 10.1096/fj.06-7227rev Papers PMCID: PMC3119634 EMSID: UKMS35683 PMID: 17267386 Resolution of inflammation: state of the art, definitions and terms Charles N. Serhan,*,1 Sue D. Brain,† Christopher D. Buckley,‡ Derek W. Gilroy,§ Christopher Haslett,||Luke A. J. O’Neill,¶ Mauro Perretti,** Adriano G. Rossi,|| and John L. Wallace†† Author information Copyright and License information Disclaimer The publisher's final edited version of this article is available at FASEB J See other articles in PMC that cite the published article. Go to: Abstract A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution. Keywords: anti-inflammatories, leukocytes, lipid mediators, chemokines, cytokines Go to: KEY CELL TYPES: THE CELLULAR PLAYERS IN THE STAGE OF RESOLUTION In response to injury or infection, specialized, “front-line” leukocytes (polymorphonuclear neutrophils (PMNs) and eosinophils) migrate to infected/damaged sites to neutralize and eliminate potentially injurious stimuli. This requirement is perhaps the most obvious but undeniably critical one for acute inflammation to resolve. Dispensing with the inciting stimulus will halt further pro-inflammatory mediator synthesis (eicosanoids, chemokines, cytokines, cell adhesion molecules, etc.) and lead to their catabolism and the curtailment of pro-inflammatory signaling pathways (Fig. 1). Toll-like receptors are now held to play essential roles in the recognition of many of these invading organisms (vide infra). This, coupled with the release of factors that prevent ongoing PMN/eosinophil trafficking and edema formation, hails the beginning of the end—namely resolution of the acute inflammatory response and return to normal homeostasis. Open in a separate window Figure 1 Schematic depicting the cellular and molecular components of the inflammatory response and the requirements for resolution. A) (adapted from Cotran; see ref. 1) depicts the cellular and histological changes that occur in tissues following an inflammatory insult. Acute inflammation is characterized by the extravascular accumulation of neutrophils (PMN) and edema formation early in the response. Later during the response, mononuclear cells and macrophages accumulate and help prepare the tissue for resolution. B, C) Represent the role that specific molecular mediators play in these events. In (B), we highlight that early on in the inflammatory response, immediate and early sequential pre-dominately pro-inflammatory mediators are released, which initiate and augment the acute-phase of the response (green lights). However, this is counterbalanced by endogenous anti-inflammatory signals such as corticosterone, which serve to temper the severity and limit the duration of the early onset phase. As inflammation progresses, certain “stop signals” at appropriate “checkpoints” prevent further leukocyte traffic into tissue. These stop signals include the lipoxins, Resolvins, and prostaglandins (PGs) of the D series and pave the way for monocyte migration and their differentiation to phagocytosing macrophages, which remove dead cells and then exit the site of inflammation. Stromal cells such as fibroblasts also contribute to the resolution of inflammation by the withdrawal of survival signals and the normalization of chemokine gradients, thereby allowing infiltrating leukocytes to undergo apoptosis or leave the tissue through the draining lymphatics. This sequential set of responses leads to complete resolution and, importantly, the restoration of the inflamed tissue to its prior physiological functioning. This is the ideal sequence of events in physiological inflammation, which contrast to the situation in pathological inflammation (B) where some of the factors that initiate the resolution program lead to the inappropriate accumulation of leukocytes in the wrong place at the wrong time. One traditional view argued that pro-inflammatory mediator catabolism was sufficient for inflammation to switch off and the response subsequently just “fizzled out” (1). This is only part of the process at the tissue level, as PMN or eosinophils if left unchecked could do untold harm to an already inflamed site and must be disposed of in a controlled and effective manner. Thus, next in the sequence of events is cell clearance. The exit routes available to inflammatory leukocytes include systemic recirculation (less well described) or local death followed by their phagocytosis by recruited monocyte-derived macrophages. Once phagocytosis is complete, macrophages exit the inflamed site by lymphatic drainage with evidence that a small population may die locally by apoptosis. If all of these pathways are strictly followed, then acute inflammation will resolve without causing excessive tissue damage and give little opportunity for the development of acute, ongoing inflammation and its associated complications. The last but equally essential aspect in the quest for tissue resolution and homeostasis is that the parenchymal/stromal cells that hosted the inflammatory event revert back to a non-inflammatory phenotype (2). Most current therapies target immune cells in an attempt to inhibit the production of pro-inflammatory chemical mediators. However, an equally important target is the active induction of proresolution programs by stromal cells such as fibroblasts within the inflamed tissues (2). As with the onset phase of acute inflammation, each of the above steps in the quest for resolution is also highly coordinated and under the tight control of what may be called “proresolution” factors (3). These factors and their importance in controlling inflammation have become apparent only in the past few years (Fig. 1A, B). Here, we discuss the state of the research in this field as its stands today and highlight the virtues of “resolution” and why we trust that understanding it in molecular terms may help us in the quest for new drugs to treat inflammatory diseases. Go to: CHEMICAL MEDIATORS IN RESOLUTION Indeed, a number of recent reports have heightened the awareness that resolution is an active process, one that requires activation of endogenous programs that enable the host tissue to maintain homeostasis (3-5). In this paper, we shall underscore current topics and definitions of components in resolution as well as outline where gaps in information lie within this new field. It is apparent that inflammation plays an important role in the pathophysiology of many common diseases that affect Western civilizations, including some degenerative diseases not previously thought to have inflammatory components, such as Alzheimer’s and atherosclerosis. Thus, the cellular mechanisms by which resolution occurs and the key biochemical pathways associated (8) with the return to homeostasis/catabasis (return from disease) clearly open many new avenues for potential therapeutic interventions in a wide range of diseases associated with unresolved inflammation. These will surely aid in our understanding of innate immunity and clearance of microbes. Go to: “ANTI-INFLAMMATORY” VS. “PRO-RESOLUTION” The notion that the inflammatory response generates its own regulators in tandem with the better-known pro-inflammatory mediators and pathways makes sense teleologically: From the cybernetic viewpoint it is easier to control a process with both positive and negative regulatory inputs (Fig. 1B). Or perhaps a finer level of control can be achieved; for example, consider the car metaphor of hitting the brakes to stop or the accelerator to go. Indeed, several endogenous regulators of the inflammatory response have already been elucidated (for reviews, see refs. 3-5), adding support to the idea that this is a widely employed mechanism. Clearly, disturbances in such counter-regulatory circuits could lead to exacerbated inflammatory responses just as effectively (although perhaps less obviously) than excessive activation of the pro-inflammatory cascades (6). Noteworthy, one of the most widely used classes of anti-inflammatory and immunosuppressive drugs, the glucocorticoids, have been developed from the pioneering work of Philip Hench and represents the first successful exploitation of an endogenous anti-inflammatory mediator, cortisol. Go to: RESOLUTION OF ACUTE INFLAMMATION: WHAT WE KNOW TODAY Although resolution in cellular and molecular terms has been known to pathologists at the tissue level for more than 100 years, only recently have we begun to take note. Resolution of acute inflammation, or its ideal outcome, would be complete resolution. The return to homeostasis by the tissue was thought to occur by passive mechanisms. Expressly, on surgical trauma, tissue, or chemical injury, the liberated chemical mediators (exogenous and/or endogenous) would evoke leukocyte chemotaxis into tissue. The decrease in chemotactic gradients or “the burning out” of the initial signals was thought to eventually dissipate depending on the magnitude of the invading microbes and/or injury. Resolution of acute inflammation via the exodus of neutrophils from tissues after their infiltration and involvement in host defense, namely, after the job is done, was thought to be a passive series of events (Fig. 1). The uncovering of several distinct biochemical pathways that are actively turned on during inflammation in the resolution phase, i.e., when the numbers of neutrophils infiltrating from the tissues are dropping and are actively pushed back by the mediators produced (3), provides clear evidence for the role of active biochemical pathways in resolution. The resolution phase can be defined at the histological level as the interval from maximum neutrophilic infiltration to the point when they are lost from the tissue. Concomitantly, mononuclear cells are then introduced in a nonphlogistic fashion and play a key role in tissue repair. They, too, are eventually lost from the tissue and are not found in tissue sections following neutralization of the insult. These cellular terms and temporal relationships (1, 7) have now called for the need to introduce quantitative indices, which enable us to define the precise changes in leukocytic traffic and biochemical pathways activated in exudates, as well as determine the impact of various endogenous mediators, exogenous compounds, and potential drugs within the resolution phase (8, 9). Along with these temporal changes in the quantity and quality of the leukocyte infiltrate, additional new approaches are needed to define how infiltrating cells change the stromal microenvironment and thereby affect the timing of tissue repair and remodeling (10). Go to: TOLL-LIKE RECEPTORS, NOD-LIKE RECEPTORS, AND RESOLUTION The initiation of the inflammatory response during infection or in response to sterile tissue injury involves two families of receptors, the toll-like receptors (TLRs) and nod-like receptors (NLRs) (11). TLRs recognize a range of microbial products, the best characterized is TLR4, which senses lipopolysaccharide (LPS), and TLR2, which senses bacterial lipoproteins. NLRs also sense bacterial products, the best characterized are NOD1 and NOD2, which sense peptidoglycan breakdown products, and Nalp3 (also termed cryopyrin), which is required for caspase-1 activation by several types of bacteria. Nalp3 occurs in an inflammasome complex with caspase-1, ASC, cardinal, and Nalp2 (12). The activation of the inflammasome requires TLR priming. TLRs and NLRs also sense products of inflamed tissue, and notable examples are the sensing of low MW hyaluronic acid fragments by TLR2 and TLR4 (13) and the sensing of uric acid by Nalp3 (14). Uric acid is the causative agent of gout but is also released by damaged cells, possibly as a general signal for inflammation (15). All of these represent substantial progress toward understanding innate immunity and inflammation. Regarding resolution of inflammation, in the past two years more than 25 inhibitors of TLR and NLR action have been described, which are all induced by TLRs and therefore act as negative-feedback inhibitors (16). In effect, TLRs sow the seeds of their own destruction, and the role of negative regulators clearly indicates how robust the TLR system is. Examples include splice variants of signaling proteins such as MyD88s, cell surface receptors acting as decoys such as ST2 and SIGIRR, protein phosphatases such as MKP-1, and proteins such as Triad3a that promote degradation of TLRs (16). Deletion of genes encoding these proteins leads to a hyperin-flamed state, as revealed for example by increased infiltration of neutrophils following LPS challenge in MKP-1 deficient mice (17). Similarly, inhibitors of NLRs have been found, such as caspase recruitment domain (CARD)-only protein (COP) or inhibitor of pro-caspase-1 activation (ICEBERG). Once TLRs or NLRs are triggered, their effects will ultimately be limited, allowing resolution to proceed. It is also possible that inflammation will become chronic, however, if the system is somehow dysregulated. An example here is the work of Noble and colleagues, who have shown that polymeric hyaluronic acid binds TLR2 and TLR4 and generates a protective signal in the epithelium in lung (13). Fragments of hyaluronic acid, however, generated in response to tissue injury, become inflammatory, again via TLR2 and TLR4 via an unknown mechanism. This in turn will lead to the further breakdown of hyaluronic acid via induction of hyaluronidases, promoting further inflammation. This might turn into a vicious circle, leading to chronicity, particularly if there is a defect in negative regulation due to polymorphisms in the negative regulator. Another example concerns regulatory T cells (T regs) (18, 19). These cells inhibit immunity and also suppress inflammation. During bacterial infection, TLR2 ligands are sensed by TLR2 on both T regs and macrophages. The T regs expand but are kept inhibited. TLR2 in macrophages promotes host defense, which leads to bacterial clearance. Once the TLR2 ligands have been removed, the “brake” is removed from the T regs. They produce IL10, limit inflammation, presumably promote resolution, and importantly prevent autoimmunity. These recent results provide insight into the resolution process and how it might become dysregulated, leading to chronic inflammation.
