Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.

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Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

International Journal of Molecular Sciences ◽

10.3390/ijms21082736 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2736 ◽

Cited By ~ 4

Author(s):

Young-Su Yi

Keyword(s):

Inflammatory Response ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Protective Mechanism ◽

The Novel ◽

Multiprotein Complex ◽

Novel Therapeutics ◽

Underlying Mechanisms ◽

Insight Into

Inflammation is a body’s protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps—a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of ‘canonical’ inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as ‘non-canonical’ inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.

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Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives

Biomolecules ◽

10.3390/biom12010075 ◽

2022 ◽

Vol 12 (1) ◽

pp. 75

Author(s):

Layara Roberta Ferreira Duarte ◽

Vanessa Pinho ◽

Barbara Maximino Rezende ◽

Mauro Martins Teixeira

Keyword(s):

Graft Versus Host Disease ◽

Tissue Damage ◽

Inflammatory Responses ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Resolution Of Inflammation ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Potential Use

Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.

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p38/AP-1 Pathway in Lipopolysaccharide-Induced Inflammatory Responses Is Negatively Modulated by Electrical Stimulation

Mediators of Inflammation ◽

10.1155/2013/183042 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Deok Jeong ◽

Jaehwi Lee ◽

Young-Su Yi ◽

Yanyan Yang ◽

Kyoung Won Kim ◽

...

Keyword(s):

Electrical Stimulation ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Physiological Role ◽

Peritoneal Macrophages ◽

Cellular Level ◽

Transcriptional Level ◽

Weak Current ◽

Anti Inflammatory

Electrical stimulation with a weak current has been demonstrated to modulate various cellular and physiological responses, including the differentiation of mesenchymal stem cells and acute or chronic physical pain. Thus, a variety of investigations regarding the physiological role of nano- or microlevel currents at the cellular level are actively proceeding in the field of alternative medicine. In this study, we focused on the anti-inflammatory activity of aluminum-copper patches (ACPs) under macrophage-mediated inflammatory conditions. ACPs generated nanolevel currents ranging from 30 to 55 nA in solution conditions. Interestingly, the nanocurrent-generating aluminum-copper patches (NGACPs) were able to suppress both lipopolysaccharide-(LPS-) and pam3CSK-induced inflammatory responses such as NO and PGE2production in both RAW264.7 cells and peritoneal macrophages at the transcriptional level. Through immunoblotting and immunoprecipitation analyses, we found that p38/AP-1 could be the major inhibitory pathway in the NGACP-mediated anti-inflammatory response. Indeed, inhibition of p38 by SB203580 showed similar inhibitory activity of the production of TNF-αand PGE2and the expression of TNF-αand COX-2 mRNA. These results suggest that ACP-induced nanocurrents alter signal transduction pathways that are involved in the inflammatory response and could therefore be utilized in the treatment of various inflammatory diseases such as arthritis and colitis.

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Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms23020732 ◽

2022 ◽

Vol 23 (2) ◽

pp. 732

Author(s):

Katrin Peckert-Maier ◽

Dmytro Royzman ◽

Pia Langguth ◽

Anita Marosan ◽

Astrid Strack ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Transplant Rejection ◽

Immune Checkpoints ◽

Potential Candidate ◽

Resolution Of Inflammation ◽

Checkpoint Molecule

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.

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Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v19i4.4130 ◽

2020 ◽

Author(s):

Zohreh Jadali

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Relevant Literature ◽

Regulatory Mechanisms ◽

Immune Mediated ◽

Key Factor ◽

Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

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Repair and recovery mechanisms following critical illness

10.1093/med/9780199600830.003.0309 ◽

2016 ◽

Author(s):

Geoffrey Bellingan ◽

Brijesh V. Patel

Keyword(s):

Critical Illness ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Structure And Function ◽

Tissue Structure ◽

Inflammatory Activation ◽

Recovery Mechanisms ◽

And Function

Inflammation is the beneficial host response to foreign challenge or tissue injury that ultimately leads to the restoration of tissue structure and function. Critical illness is associated with an overwhelming and prolonged inflammatory activation. Resolution of the inflammatory response is an active process that requires removal of the inciting stimuli, cessation of the pro-inflammatory response, a timely coordinated removal of tissue leukocyte infiltration, a conversion from ‘toxic’ to reparative tissue environment, and restoration of normal tissue structure and function. Mortality may result from deficits in these resolution mechanisms. Improved delivery of critical care through prevention of harm and removal of stimuli has already delivered significant mortality benefits. Most critically-ill patients present with uncontrolled inflammation, hence anti-inflammatory strategies ameliorating this response are likely to be too late and thus futile. Rather, strategies augmenting endogenous pathways involved in the control and appropriate curtailment of such inflammatory responses may promote resolution, repair, and catabasis. Recent evidence showing that inflammation does not simply ‘fizzle out’, but its resolution involves an active and coordinated series of events. Dysfunction of these resolution checkpoints alters the normal inflammatory pathway, and is implicated in the induction and maintenance of states such as ARDS and sepsis. Improved understanding of resolution biology should provide translational pathways to not only improve survival, but also to prevent long-term morbidity resulting from tissue damage.

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Inflammation: a role for NR4A orphan nuclear receptors?

Biochemical Society Transactions ◽

10.1042/bst0390688 ◽

2011 ◽

Vol 39 (2) ◽

pp. 688-693 ◽

Cited By ~ 109

Author(s):

Jason P. McMorrow ◽

Evelyn P. Murphy

Keyword(s):

Inflammatory Response ◽

Nuclear Receptors ◽

Acute Phase ◽

Immune Cells ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Tissue Injury ◽

Chronic Phase ◽

Psoriatic Skin ◽

Orphan Nuclear Receptors

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.

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Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Cellular Physiology and Biochemistry ◽

10.1159/000492885 ◽

2018 ◽

Vol 49 (1) ◽

pp. 349-358 ◽

Cited By ~ 20

Author(s):

Wei-Yu Chen ◽

Tzu-Hsien Tsai ◽

Jenq-Lin Yang ◽

Lung-Chih Li

Keyword(s):

T Cells ◽

Immune Responses ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Lymphoid Cells ◽

Gastrointestinal System ◽

Immune Functions ◽

Central Nerve System ◽

Nerve System

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

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Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.620984 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yufei Xie ◽

Annemarie H. Meijer ◽

Marcel J. M. Schaaf

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Critical Role ◽

Model Systems ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammatory Drugs ◽

Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

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Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

Cardiovascular Research ◽

10.1093/cvr/cvz221 ◽

2019 ◽

Vol 116 (7) ◽

pp. 1357-1371 ◽

Cited By ~ 10

Author(s):

Laura Bevan ◽

Zhi Wei Lim ◽

Byrappa Venkatesh ◽

Paul R Riley ◽

Paul Martin ◽

...

Keyword(s):

Inflammatory Response ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Tissue Injury ◽

Cardiac Injury ◽

Repair Process ◽

Adult Zebrafish ◽

Cardiac Damage ◽

Scar Resolution ◽

Macrophage Subsets

Abstract Aims A robust inflammatory response to tissue injury is a necessary part of the repair process but the deposition of scar tissue is a direct downstream consequence of this response in many tissues including the heart. Adult zebrafish not only possess the capacity to regenerate lost cardiomyocytes but also to remodel and resolve an extracellular scar within tissues such as the heart, but this scar resolution process remains poorly understood. This study aims to characterize the scarring and inflammatory responses to cardiac damage in adult zebrafish in full and investigate the role of different inflammatory subsets specifically in scarring and scar removal. Methods and results Using stable transgenic lines, whole organ imaging and genetic and pharmacological interventions, we demonstrate that multiple inflammatory cell lineages respond to cardiac injury in adult zebrafish. In particular, macrophage subsets (tnfα+ and tnfα−) play prominent roles with manipulation of different phenotypes suggesting that pro-inflammatory (tnfα+) macrophages promote scar deposition following cardiac injury whereas tnfα− macrophages facilitate scar removal during regeneration. Detailed analysis of these specific macrophage subsets reveals crucial roles for Csf1ra in promoting pro-inflammatory macrophage-mediated scar deposition. Additionally, the multifunctional cytokine Osteopontin (Opn) (spp1) is important for initial scar deposition but also for resolution of the inflammatory response and in late-stage ventricular collagen remodelling. Conclusions This study demonstrates the importance of a correctly balanced inflammatory response to facilitate scar deposition during repair but also to allow subsequent scar resolution, and full cardiac regeneration, to occur. We have identified Opn as having both pro-fibrotic but also potentially pro-regenerative roles in the adult zebrafish heart, driving Collagen deposition but also controlling inflammatory cell resolution.

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