Novel Mechanisms in Resolution of Inflammation

Agenda

*Presentation times are subject to change.

Abstracts

Mechanisms and Consequences of Defective Inflammation Resolution in Atherosclerosis

Ira Tabas, MD, PhD, Columbia University, New York, NY

A majoring driving force in the progression of atherosclerosis is a maladaptive inflammatory response that fails to resolve.  Two major features of this pathological scenario include macrophage (Mø) apoptosis and defective phagocytic clearance ("efferocytosis") of the dead Møs, which, in combination, lead to formation of the necrotic core. Necrotic cores promote plaque disruption, which in turn triggers acute atherothrombotic vascular events. With regard to advanced lesional Mø apoptosis, our studies have implicated a two-hit model involving endoplasmic reticulum (ER) stress and pattern recognition receptor (PRR) signaling. The ER stress hit is mediated in part by the transcription factor CHOP, which is abundantly expressed in vulnerable but not early-stage human coronary artery lesions. Using Western diet-fed Apoe-/- and Ldlr-/- mice, we showed that genetic deletion of CHOP decreases both Mø death and plaque necrosis in advanced aortic root plaques. Mechanistic studies revealed that CHOP promotes apoptosis by inducing ER oxidase 1α (ERO1α), which stimulates release of Ca²⁺ from ER stores via activation of IP3 receptors. The released Ca²⁺ activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which is the key integrator of downstream apoptotic pathways in these cells. The PRR hit can be carried out by two receptor combinations: type A scavenger receptor (SRA)-Toll-like receptor 4 (TLR4) or CD36-TLR2. The latter can be activated by oxidized phospholipids (oxPLs) and oxidized LDL. Lipoprotein(a) [Lp(a)], a major carrier of oxPLs and a potent risk factor for coronary artery disease (CAD) in humans, can also trigger CD36-TLR2-mediated apoptosis in ER-stressed Mfs, suggesting a novel mechanism for the link between Lp(a) and CAD. With regard to efferocytosis, genetically altered mice were used to show a definitive role for the receptor MerTK in the uptake of apoptotic Møs in the atheromata of fat-fed Apoe-/- mice. Most importantly, there was a marked increase in plaque necrosis in the lesions of Mertk-/-;Apoe-/- vs. Apoe-/- mice. Additional data suggest that a defect in MerTK involving ADAM protease-mediated cleavage of the receptor is associated with vulnerable plaques in human arteries. In summary, there are two critical pathways that contribute to the failure of inflammation resolution in advanced atherosclerosis and thereby promote the progression of clinically dangerous atheromata: a detrimental Mø apoptosis pathway involving ER stress and PRR activation, the latter of which is a target of the human CAD risk factor Lp(a); and a protective efferocytosis pathway involving MerTK that may become dysfunctional in advanced lesions. Therapeutic targeting of these molecular processes through novel strategies designed to enhance inflammation resolution may lead to novel strategies to prevent acute coronary syndromes in subjects with pre-existing subclinical atherosclerosis.

Novel Mechanisms in the Resolution of Acute Inflammation

Charles N. Serhan, PhD, Harvard University, Brigham & Women's Hospital

Timely resolution of the acute inflammatory response provides new insights in host defense. Using a systems approach with self-limited inflammatory exudates to map tissue events, cell traffic and identification of proteinand chemical mediators, we identified new families of potent bioactive lipid-derived mediators, coined resolvinsand protectins in resolving exudates using lipid mediators lipidomics. Each of these pro-resolving mediators controls the duration and magnitude of acute inflammation in vivo with stereospecific sites of action in the picotonanogram range. The mapping of these endogenous resolution circuits provides new avenues to harness uncontrolled inflammation and consider the molecular basis of many inflammation-associated diseases (CSerhan American Journal of Pathology 2010). This presentation will provide an overview of our recent advances on the biosynthesis and functions of this novel genus of specialized pro-resolving mediators (SPM). These structurally distinct families of local chemical mediators were originally identified in murine exudates captured during the natural self-limited resolution phase and are also produced by human isolated cells. SPM include 3 families of chemical mediators resolvins, protectins and the most recent addition, maresins. These are biosynthesized from essential omega-3 fatty acids (EPA and DHA) and possess potent multi-pronged anti-inflammatory, pro-resolving and anti-microbial actions in murine models of sepsis (Spite et al Nature vol. 461,2009). The actions of SPM proved to be potent, cell type-specific and stereoselective with isolated human cells and in animal diseases. For example, they reduce pain and regulate miRNA identified that are of interest in resolution of acute inflammation. Together, these results indicate that natural resolution pathways may underlie many prevalent diseases associated with uncontrolled inflammation and open the potential for resolution-based pharmacology. The author acknowledges support of NIH grants DE019938, NS067686, and GM038765.

Endogenous Anti-Inflammation and Resolution: Players and Receptors

Mauro Perretti, PhD, Queen Mary University of London, UK

The process of acute inflammation relies on the active engagement of a series of pro-resolving mediators which assure temporal and spatial containment of the host reaction: a pro-inflammatory phase is followed by an anti-inflammatory and pro-resolving phase in line with "the beginning programmes the end" concept. Within the network of pro-resolving mediators is emerging a pattern of biological properties, shared by a variety of players, rendering specific actions paradigmatic (e.g. promotion of efferocytosis). Harnessing endogenous homeostatic pathways can lead to innovative anti-inflammatory therapeutics with beneficial applications for chronic inflammatory pathologies.

Within this area of investigation, Lipoxin A₄ and Annexin A1 are two players able to halt leukocyte migration and promote macrophage phagocytosis of infective agents as well as apoptotic leukocytes. These effects are mediated by a specific receptor, the formyl peptide receptor type 2 (the acronym FPR2/ALX is currently used to identify the human receptor). Generation of a colony of mice deficient in the mouse orthologues of FPR2/ALX is helping elucidate the patho-physiological impact of this receptor (and its agonists) in acute inflammation providing, at the same time, proof-of-concept data for its exploitation in drug discovery programmes. 

Resolvins and Protectins in Ocular Wound Healing, Inflammation and Angiogenesis 

Karsten Gronert, PhD, UC Berkeley

The dynamic and temporally defined interplay of distinct populations of leukocytes is critical but a poorly defined feature of inflammatory events. By design inflammation is a frequent and self-resolving response that is essential for protection and integrity of all tissues. Successful execution of healthy inflammation depends on tightly regulated activation of leukocytes and their active resolution to return tissues to homeostasis. Dysregulation of this highly regulated process and stalled inflammation leads to PMN mediated tissue injury, activation of the inflammatory macrophage phenotype, transition to chronic inflammation and may promote/initiate adaptive immune responses. Hence, pathways that promote the resolution of PMN are of primary interest. Their function and regulation in the eye is just beginning to unfold and of considerable interest as the delicate visual axis has evolved a highly sophisticated intrinsic and protective lipid circuit. Our studies have identified a resident lipid circuit in the cornea that counter-regulates pro-inflammatory signals, promotes wound healing, controls pathological angiogenesis and regulates dynamic in vivo leukocyte behavior. The presentation is an update on current state of the field and new developments, which demonstrate that this intrinsic protective lipid circuit is regulated by dietary PUFA and exhibits sex-specific differences. Unraveling regulation of these intrinsic protective lipid circuits may provide insights into the etiology or pathogenesis of ocular inflammatory diseases.

From Bench to Clinic: Resolvins as New Therapeutics

Per Gjorstrup, MD, PhD, Resolvyx Pharmaceuticals

Existing preclinical data now indicate that resolvins and protectins, either as their natural endogenous mediators, or as synthetic analogs, present a huge potential as a novel treatment approach for chronic inflammatory disease. With resolvins being first-in-class lead compounds several requirements had to be met in the selection of a proof-of-concept indication, not least due to the complex and redundant pathologies commonly seen in inflammatory disease. The choice was made to develop a first drug candidate for the treatment of dry eye disease. Dry eye is an inflammatory condition provoked by environmental stresses due to loss of the protective tear film. It involves activation of both innate and in severe cases the adaptive immune systems, as well as epithelial activation with release of proinflammatory mediators. The opportunity to investigate all these aspects of inflammation in an approach using murine models of eye inflammation combined with investigations of inflammatory mediator release and tissue survival using human corneal cells, created a unique drug development opportunity. The easy access to eye tissue allowed the direct assessment of dose required to achieve therapeutic drug concentrations in the relevant target tissue, and together with in vivo and in vitro pharmacological data supported the development of an algorithm to select doses for the first successful human clinical phase 2 study based on the resolvin concept, and will be presented. The relevance of this approach for dose selection when moving a systemically delivered resolvin into phase 2 clinical studies will also be discussed.

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