The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification Abstract Omega-3 fatty acids serve as the substrate for the formation of a group of lipid mediators that mediate the resolution of inflammation. The cardiovascular inflammatory response in atherosclerosis and vascular injury is characterized by a failure in the resolution of inflammation, resulting in a chronic inflammatory response. The proresolving lipid mediator resolvin E1 (RvE1) is formed by enzymatic conversion of the omega-3 fatty acid eicosapentaenoic acid (EPA), and signals resolution of inflammation through its receptor ChemR23. Importantly, the resolution of cardiovascular inflammation is an active, multifactorial process that involves modulation of the immune response, direct actions on the vascular wall, as well as close interactions between macrophages and vascular smooth muscle cells. Promoting anti-atherogenic signalling through the stimulation of endogenous resolution of inflammation pathways may provide a novel therapeutic strategy in cardiovascular prevention.

Resolution of inflammation during multiple sclerosis Abstract Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS). There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses. Inflammation is present in all subsets of MS. The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS. Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS. Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor. In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution. Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.

Resolution of uveitis Abstract Autoimmune uveitis is a sight-threatening, rare disease, potentially leading to blindness. Uveitis is a synonym for intraocular inflammation, presenting as various clinical phenotypes with different underlying immune responses in patients, whereas different animal models usually represent one certain clinical and immunological type of uveitis due to genetic uniformity and the method of disease induction. T cells recognizing intraocular antigens initiate the disease, recruiting inflammatory cells (granulocytes, monocytes/macrophages) to the eyes, which cause the damage of the tissue. The treatment of uveitis so far aims at downregulation of inflammation to protect the ocular tissues from damage, and at immunosuppression to stop fueling T cell reactivity. Uveitis is usually prevented by specific mechanisms of the ocular immune privilege and the blood-eye-barriers, but once the disease is induced, mechanisms of the immune privilege as well as a variety of novel regulatory features including new Treg cell populations and suppressive cytokines are induced to downregulate the ocular inflammation and T cell responses and to avoid relapses and chronicity. Here we describe mechanisms of regulation observed in experimental animal models as well as detected in studies with peripheral lymphocytes from patients.

Towards a pro-resolving concept in systemic lupus erythematosus Abstract Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death–related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.

Resolution of Crohn’s disease Abstract Crohn’s disease (CD) is characterized by chronic inflammation of the gastrointestinal tract and represents one of the main inflammatory bowel disease (IBD) forms. The infiltration of immune cells into the mucosa and uncontrolled production of pro-inflammatory cytokines and other mediators trigger the chronic inflammatory reaction in the intestine [1]. The inflammatory setting consists of subsequent events that comprise an induction phase, the peak of inflammation which is subsequently followed by the resolution phase. The induction phase, which represents the first phase of inflammation, is important for the rapid and efficient activation of the immune system for sufficient host defense. The permanent sensing of exogenous or endogenous danger signals enables the fast initiation of the inflammatory reaction. The immune cell infiltrate initiates an inflammatory cascade where released lipid and protein mediators play an indispensable role [2, 3]. The last decades of research strongly suggest that resolution of inflammation is similarly a tightly coordinated and active process. The basic concept that resolution of inflammation has to be regarded as an active process has been thoroughly described by others [4–6]. The following review focuses on mechanisms, pathways, and specific mediators that are actively involved in the resolution of inflammation in CD.

Resolution of inflammation in arthritis Abstract Rheumatoid arthritis is among the most frequent and severe chronic inflammatory diseases. The disease is characterized by ongoing synovial inflammation, which leads to the destruction of cartilage and bone. In RA, the mechanisms of resolution of inflammation, which are normally intact in the joints, are either suppressed or overruled. Little efforts have been undertaken to understand the mechanisms of resolution of arthritis until recently, when several molecular mechanisms have been identified that determine the chronicity and resolution of inflammation in the joints, respectively. This review describes the key concepts of resolution of arthritis mentioning the key mechanisms involved, such as regulatory macrophages, pro-resolving lipid, fatty acid and cytokine mediators, aggregated neutrophil extracellular trap formation, antibody glycosylation changes, and stromal cell alterations that are involved in determining the decision between chronicity and resolution of arthritis. Each of these mechanisms represents a potential therapeutic approach that allows skewing the balance of the inflammatory processes towards resolution.

Resolution of ulcerative colitis Abstract Ulcerative colitis designates an idiopathic chronic inflammatory bowel disease leading to bloody diarrhea and inflammatory alterations mostly restricted to the large intestine. Many studies continue to unravel important aspects of its etiopathogenesis, and recent pharmaceutical developments broaden the arsenal of therapeutic opportunity. In this review, we delve into the cellular and molecular determinants of successful resolution of ulcerative colitis, describing novel insights in each of the phases of mucosal healing starting from damaging insults to the mucosa, epithelial restitution, and its adaption to inflammation as well as lymphocyte-driven maintenance and resolution of chronic inflammation. Additionally, molecular switches from inflammation to resolution are explored, paving the way for future avenues to resolve ulcerative colitis.

Resolution of allergic asthma Abstract Allergic asthma is an inflammatory disease of the airways characterized by recurrent episodes of wheezing and bronchoconstriction. Chronic inflammation may finally lead to structural damage followed by airway remodeling. Various studies in recent years contributed to unravel important aspects of the immunopathogenesis of asthma and adapted new pharmaceutical developments. Here, I consider some novel insights into the immunopathogenesis of asthma and the protective and pathogenic roles of some innate and adaptive immune cells as well as the function of soluble mediators such as cytokines. Particular attention will be given to new concepts on resolution of chronic airway inflammation for prevention of airway structural damage.

Resolution in bullous pemphigoid Abstract Pemphigoid diseases are a group of autoimmune blistering skin diseases defined by an immune response against certain components of the dermal-epidermal adhesion complex. They are prototypical, autoantibody-driven, organ-specific diseases with the emergence of inflammatory skin lesions dependent on the recruitment of immune cells, particularly granulocytes, into the skin. During an acute flare of disease, inflammatory skin lesions typically progressing from erythema through urticarial plaques to subepidermal blisters erosions erupt and, finally, completely resolve, thus illustrating that resolution of inflammation is continuously executed in pemphigoid disease patients and can be directly monitored on the skin. Despite these superb conditions for examining resolution in pemphigoid diseases as paradigm diseases for antibody-induced tissue inflammation, the mechanisms of resolution in pemphigoid are underinvestigated and still largely elusive. In the last decade, mouse models for pemphigoid diseases were developed, which have been instrumental to identify several key pathways for the initiation of inflammation in these diseases. More recently, also protective pathways, specifically IL-10 and C5aR2 signalling on the molecular level and Tregs on the cellular level, counteracting skin inflammation have been highlighted and may contribute to the continuous execution of resolution in pemphigoid diseases. The upstream orchestrators of this process are currently under investigation. Pemphigoid disease patients, particularly bullous pemphigoid patients, who are predominantly above 75 years of age, often succumb to the side effects of the immunosuppressive therapeutics nowadays still required to suppress the disease. Pemphigoid disease patients may therefore represent a group of patients benefiting most substantially from the introduction of non-immunosuppressive, proresolving therapeutics into the treatment regimens for their disease.

Resolution of plaque-type psoriasis: what is left behind (and reinitiates the disease) Abstract Psoriasis is a chronic inflammatory skin disease that involves numerous types of immune cells and cytokines resulting in an inflammatory feedback loop and hyperproliferation of the epidermis. A more detailed understanding of the underlying pathophysiology has revolutionized anti-psoriatic treatment and led to the development of various new drugs targeting key inflammatory cytokines such as IL-17A and IL-23. Successfully treated psoriatic lesions often resolve completely, leaving nothing visible to the naked eye. However, such lesions tend to recur within months at the exact same body sites. What is left behind at the cellular and molecular levels that potentially reinitiates psoriasis? Here, we elucidate the cellular and molecular “scar” and its imprints left after clinical resolution of psoriasis treated with anti-TNFα, anti-IL-17, or anti-IL-23 antibodies or phototherapy. Hidden cytokine stores and remaining tissue-resident memory T cells (TRMs) might hold the clue for disease recurrence.