Resolution of inflammation pathways in preeclampsia—a narrative review

Preeclampsia (PE) is one of the leading causes of maternal morbidity and mortality worldwide. This disease is believed to occur in two stages with placental dysfunction in early pregnancy leading to maternal clinical findings after 20 weeks of gestation, as consequence of systemic inflammation, oxidative stress, and endothelial dysfunction. Much evidence suggests that PE women display an overshooting inflammatory response throughout pregnancy due to an unbalanced regulation of innate and adaptive immune responses. Recently, it has been suggested that dysregulation of endogenous protective pathways might be associated with PE etiopathogenesis. Resolution of inflammation is an active process coordinated by mediators from diverse nature that regulate key cellular events to restore tissue homeostasis. Inadequate or insufficient resolution of inflammation is believed to play an important role in the development of chronic inflammatory diseases, like PE. In this narrative review, we discuss possible pro-resolution pathways that might be compromised in PE women, which could be targets to novel therapeutic strategies in this disease.     

"Pro-resolution" and anti-inflammation, a role of RvE1 in anti-atherosclerosis and plaque stabilization

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.     

The resolution of inflammation: Principles and challenges

The concept that chemokines, cytokines and pro-inflammatory mediators act in a co-ordinated fashion to drive the initiation of the inflammatory reaction is well understood. The significance of such networks acting during the resolution of inflammation however is poorly appreciated. In recent years, specific pro-resolving mediators were discovered which activate resolution pathways to return tissues to homeostasis. These mediators are diverse in nature, and include specialized lipid mediators (lipoxins, resolvins, protectins and maresins) proteins (annexin A1, galectins) and peptides, gaseous mediators including hydrogen sulphide, a purine (adenosine), as well as neuromodulator release under the control of the vagus nerve. Functionally, they can act to limit further leukocyte recruitment, induce neutrophil apoptosis and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to the lymphatics and help initiate tissue repair mechanisms and healing. Within this review we highlight the essential cellular aspects required for successful tissue resolution, briefly discuss the pro-resolution mediators that drive these processes and consider potential challenges faced by researchers in the quest to discover how inflammation resolves and why chronic inflammation persists.     

Chronic inflammation: a failure of resolution?

Inflammation has evolved as a protective response to insult or injury, it's a primordial response that eliminates or neutralises foreign organisms or material, the resolution of inflammation encompasses the endogenous anti-inflammatory mechanisms that protect us against excessive tissue injury and promote the restoration of tissue structure and function. In fact, our well being and survival depends upon its efficiency and carefully-balanced control. In general, the innate inflammatory response initiates within minutes and, if all is well, resolves within hours. In contrast, chronic inflammation persists for weeks, months or even years. Here, we are going to discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence.     

Neutrophils and inflammatory resolution in the mucosa

Inflammatory diseases in mucosal organs as diverse as the lung, liver and intestine inevitably require the intimate interactions between neutrophils and epithelia. The physiologic consequences of such interactions often determine endpoint organ function, and for this reason, much recent interest has developed in identifying mechanisms and novel targets to promote the resolution of mucosal inflammation. Physiologically-relevant in vitro and in vivo model systems have aided in discovery of novel pathways to define basic inflammatory mechanisms and approaches to defining the concepts of inflammatory resolution. Here, we will review the recent literature regarding the contribution of neutrophils to inflammatory resolution, with an emphasis on the role of the tissue microenvironment, endogenous pathways for promoting resolution and the molecular determinants of neutrophil–epithelial cell interactions during ongoing inflammation. These recent studies highlight the dynamic nature of pro-resolving pathways and lend insight into the complexity of treating mucosal inflammation.     

Cytokine signaling modules in inflammatory responses

Cytokine signaling via a restricted number of Jak-Stat pathways positively and negatively regulates all cell types involved in the initiation, propagation, and resolution of inflammation. Here, we focus on Jak-Stat signaling in three major cell types involved in inflammatory responses: T cells, neutrophils, and macrophages. We summarize how the Jak-Stat pathways in these cells are negatively regulated by the Suppressor of cytokine signaling (Socs) proteins. We emphasize that common Jak-Stat-Socs signaling modules can have diverse developmental, pro- and anti-inflammatory outcomes depending on the cytokine receptor activated and which genes are accessible at a given time in a cell's life. Because multiple components of Jak-Stat-Socs pathways are mutated or closely associated with human inflammatory diseases, and cytokine-based therapies are increasingly deployed to treat inflammation, understanding cytokine signaling will continue to advance our ability to manipulate chronic and acute inflammatory diseases.     

Resolution of inflammation

Acute inflammatory reactions, in contrast to chronic inflammatory reactions, are usually self-limiting and resolve. We have investigated the resolving phase of a number of immune and non-immune inflammatory reactions induced in the pleural cavity of rats. COX-2 is expressed during resolution of these models. Using carrageenan pleurisy, we showed that this enzyme has a proinflammatory role as the reaction develops but an antiinflammatory role as the lesion resolves. This antiinflammatory role is associated with production of cyclopentenone prostaglandins and the absence of PGE2. Dual COX-1/COX-2 inhibitors or COX-2 inhibitors when given at the peak of the inflammatory response delay resolution, an effect reversed by replacing CyPGs into the pleural space. PGF2alpha like the CyPGs appears to have a role in resolving this reaction. Stress proteins are also induced in a variety of acute inflammatory models during resolution. Heme oxygenase-1 (HO-1) is one such protein so too are members of the hsp70 family. An inducer of HO-1 promotes resolution whereas an inhibitor is proinflammatory. In most cases it appears to be the macrophage that is the source of proteins necessary for resolution to occur. Understanding how proinflammatory pathways switch to the antiinflammatory pathways necessary for resolution to take place may eventually allow the exploitation of endogenous antiinflammatory pathways in the treatment of chronic inflammation.     

Contributions of neutrophils to resolution of mucosal inflammation

Neutrophil (PMN) recruitment from the blood stream into surrounding tissues involves a regulated series of events central to acute responses in host defense. Accumulation of PMN within mucosal tissues has historically been considered pathognomonic features of both acute and chronic inflammatory conditions. Historically, PMNs have been deemed necessary but detrimental when recruited, given the potential for tissue damage that results from a variety of mechanisms. Recent work, however, has altered our preconceived notions of PMN contributions to inflammatory processes. In particular, significant evidence implicates a central role for the PMN in triggering inflammatory resolution. Such mechanisms involve both metabolic and biochemical crosstalk pathways during the intimate interactions of PMN with other cell types at inflammatory sites. Here, we highlight several recent examples of how PMN coordinate the resolution of ongoing inflammation, with a particular focus on the gastrointestinal mucosa.     

Chronic inflammation in asthma: a contest of persistence vs resolution

Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.     

Endogenous pro-resolving and anti-inflammatory lipid mediators: the new hope of atherosclerotic diseases

Atherosclerosis is a complex disease process in which genetic, lipid, cellular, and immunological factors combine to determine the location, severity, and timing of lesion development and clinical events. It has been demonstrated, however, that inflammation governed atherosclerosis during the course of development of atherosclerosis. It has also been demonstrated to be effective to decrease the cardiovascular events and improve the prognosis of atherosclerotic diseases by regulating inflammatory reaction (e.g., statins). However, endogenous mechanisms of limiting inflammation in atherosclerosis are still unclear. Recent studies showed that lipoxidase/leukotrienes (LOX/LTs) pathway played important role in the ignition and development of atherosclerosis, whereas resolvins (E-series resolvins and D-series resolvins) and protectins [protectin D1 (PD1) and neuroprotectin D1 (NPD1)], endogenous lipid-derived mediators, inhibited inflammation through pro-resolution and counter-modulating immune inflammation reaction in atherosclerosis. Hence, we hypothesize that increased endogenous lipid mediators mentioned above play a vital role in anti-atherosclerosis and plaque stabilization through pro-resolution and anti-inflammation by LOX/LTs pathway. In addition, we predict that the endogenous lipid mediators may be a new target for treatment of atherosclerotic diseases.     

Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation

Interleukin 23 (IL-23) is integral to the pathogenesis of chronic inflammation. The resolution of acute inflammation is an active process mediated by specific signals and mediators such as resolvin E1 (RvE1). Here we provide evidence that RvE1, in nanogram quantities, promoted the resolution of inflammatory airway responses in part by directly suppressing the production of IL-23 and IL-6 in the lung. Also contributing to the pro-resolution effects of RvE1 treatment were higher concentrations of interferon-gamma in the lungs of RvE1-treated mice. Our findings indicate a pivotal function for IL-23 and IL-6, which promote the survival and differentiation of IL-17-producing T helper cells, in maintaining inflammation and also identify an RvE1-initiated resolution program for allergic airway responses.     

Is sepsis a pro-resolution deficiency disorder?

Sepsis is due to a systemic inflammatory response to both infectious and non-infectious disorders; and when it leads to hypotension and organ dysfunction, septic shock occurs. Mortality in sepsis is due to multiple organ dysfunction. The early stages of sepsis are characterized by excessive generation of inflammatory mediators; however, as sepsis develops into chronic severe sepsis, immunosuppression dominates. Despite several advances in our understanding of the pathogenesis of sepsis both its prevention and management remains elusive. It is proposed that sepsis is due to failure of production of appropriate amounts of pro-resolution bioactive lipids such as lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inappropriate inflammation, production of pro-inflammatory cytokines, free radical generation, and leukocyte activation and enhance resolution of inflammation and wound healing.     

Pathways involved in the resolution of inflammatory joint disease

A common feature of seasonal colds and other infections is painful joints. This is due to an acute reactive inflammatory arthritis which almost always resolves. Unfortunately, for some people the inflammation never completely resolves but rather precedes progression to chronic inflammatory arthritis.The existing dogma that accounts for why chronic inflammatory joint disease persists is that it is due to an excess of pro-inflammatory signals and that resolution occurs by pro-inflammatory mediator catabolism. Recent discoveries have supported a new paradigm which proposes that the resolution of inflammation is an active process with genetic, molecular and cellular programs that promote catabasis.By seeking to understand the mechanisms behind the spontaneous resolution of inflammation, we can gain insight into why inflammation sometimes fails to resolve. This review seeks to highlight the mechanisms behind the resolution of joint inflammation and how endogenous pro-resolving mediators could be used to treat chronic persistent inflammatory joint disease.     

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R_i) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R_i; 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation.     

Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation: To Resolve or Not?

Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid–derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that anti-inflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies.     

Atherosclerosis – A matter of unresolved inflammation

Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries.     

Resolution of inflammation as a novel chemopreventive strategy

Acute inflammation, a physiologic response to protect cells from microbial infection and other noxious stimuli, is automatically terminated by endogenous anti-inflammatory and pro-resolving mediators to restore homeostatic conditions. However, if timely resolution of inflammation is failed, inflammation persists and can progress to a chronic inflammation which has long been thought as a predisposing factor to carcinogenesis. Excessive and pathologic inflammation causes DNA damage, genomic instability, epigenetic dysregulation, and alteration of intracellular signaling, all of which are involved in neoplastic transformation. To prevent chronic inflammation and resulting inflammation-promoted cancer development, understanding the process that resolves inflammation is essential. Resolution of inflammation is an active coordinated process regulated by distinct anti-inflammatory and pro-resolving endogenous lipid mediators, such as resolvins and lipoxins. The role of pro-inflammatory signaling in carcinogenesis has become more and more evident and well characterized, but the potential role of pro-resolving mediators in cancer prevention remains still elusive. In searching for an efficacious way to prevent chronic inflammation-associated cancer, the pro-resolving signal transduction pathways and their regulators should be unraveled.     

Mast cells,glia and neuroinflammation: partners in crime?

Glia and microglia in particular elaborate pro‐inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro‐inflammatory signals released from other non‐neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood–spinal cord and blood–brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell–glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non‐neuronal cells that normally control neuronal sensitization – both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up‐regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N‐acylethanolamine family. One such member, N‐palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N‐Palmitoylethanolamine has proven efficacious in mast‐cell‐mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell–microglia cross‐talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.     

Immunobiology of TNFSF15 and TNFRSF25

The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn’s disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics.     

Monocyte trafficking in acute and chronic inflammation

Environmental signals at the site of inflammation mediate rapid monocyte mobilization and dictate differentiation programs whereby these cells give rise to macrophages or dendritic cells. Monocytes participate in tissue healing, clearance of pathogens and dead cells, and initiation of adaptive immunity. However, recruited monocytes can also contribute to the pathogenesis of infection and chronic inflammatory disease, such as atherosclerosis. Here, we explore monocyte trafficking in the context of acute inflammation, relying predominantly on data from microbial infection models. These mechanisms will be compared to monocyte trafficking during chronic inflammation in experimental models of atherosclerosis. Recent developments suggest that monocyte trafficking shares common themes in diverse inflammatory diseases; however, important differences exist between monocyte migratory pathways in acute and chronic inflammation.