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

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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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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The relationship between tumour necrosis, circulating IL-6 concentrations, and inflammatory responses in patients undergoing curative resection for colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.404 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 404-404

Author(s):

Graeme JK Guthrie ◽

Campbell SD Roxburgh ◽

Colin H Richards ◽

Paul G. Horgan ◽

Donald C. Mcmillan

Keyword(s):

Colorectal Cancer ◽

Skeletal Muscle ◽

Inflammatory Response ◽

Interleukin 6 ◽

Tumour Necrosis ◽

Curative Resection ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Inflammatory Cell Infiltrate ◽

Cell Infiltrate

404 Background: Cancer-associated inflammation, in the form of systemic and local inflammation, and tumour necrosis are known to have prognostic value in colorectal cancer (CRC). In addition, recent work has reported a direct relationship between the systemic inflammatory response and loss of skeletal muscle in patients with CRC. However, the inter-relationships between these inflammatory responses, tumour necrosis, metabolic upset and circulating biochemical mediators are unclear in CRC. Interleukin-6 and its downstream signalling cascades have been implicated in both cancer-associated inflammation and cancer-associated muscle wasting. The aim of the present study was to examine whether circulating IL-6 concentrations may link tumour necrosis, local and systemic inflammatory responses, and metabolic upset in patients undergoing curative resection for colorectal cancer. Methods: The study included 118 patients undergoing surgery for CRC between 2004 and 2009. Data were collected from pre-operative blood tests. Routine pathology specimens were scored for Klintrup criteria and tumour necrosis. Results: Tumour necrosis was associated with increased T-stage (p<0.01), reduced inflammatory cell infiltrate (p<0.05), increased IL-6 (p<0.001), IL-10 (p<0.01), and VEGF (p<0.001) and with markers of the systemic inflammatory response: mGPS (p<0.001), anaemia (p<0.05); increased white cell (p<0.001), neutrophil (p<0.05) and platelet (p<0.001) counts. Circulating IL-6 was associated with increased IL-10 (p<0.01), VEGF (p<0.001), increased mGPS (p<0.001), increased white cell (p<0.01) and platelet (p<0.01) counts and low skeletal muscle index (p<0.01). On Spearman rank correlation there were significant associations between circulating concentrations of IL-6 and IL-10 (rs= 0.39, p<0.001) and CRP (r= 0.42, p<0.001). Conclusions: Interleukin-6 appears to be associated with systemic inflammation, tumour necrosis, and sarcopenia in colorectal cancer. However, the lack of an association between IL-6 and the local inflammatory response suggests a more complex relationship with the tumour inflammatory cell infiltrate.

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Abstract T P324: Sex Differences in Ischemic Outcomes and Inflammatory Responses in Neonatal Stroke

Stroke ◽

10.1161/str.45.suppl_1.tp324 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Mehwish A Mirza ◽

Kathryn Bentivegna ◽

Rodney Ritzel ◽

Kaitlyn H Hajdarovic ◽

Louise D McCullough ◽

...

Keyword(s):

Sex Differences ◽

Inflammatory Response ◽

Microglial Activation ◽

Inflammatory Responses ◽

Tissue Injury ◽

Activation Markers ◽

Male And Female ◽

Hormone Levels ◽

Time Points ◽

Cytokine Analysis

Background and Purpose: Neonatal arterial ischemic stroke (NAIS) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insult and suffer more long-term deficits than female infants though the mechanisms remain elusive. Inflammatory processes are fundamental in the pathophysiology of ischemia as microglial activation initiates the inflammatory response after ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in neonatal brains under normal conditions. How these basal sex differences in microglia affect NAIS remains largely unexplored. This study investigated sex differences in stroke phenotypes and inflammation triggered by NAIS. We hypothesize that ischemia induces sex-specific tissue injury in male and female neonates, which is related to differences in microglial activation and inflammatory responses. Methods: Male and female C57BL6 mice were subjected to 60-minute Rice-Vanucci Modeling at post-natal day 10 (P10) to induce NAIS. Stroke outcomes were measured at 24 hours, 72 hours and 7 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry, immunohistochemistry, and multiplex cytokine analysis. Results: At 24 hours no difference in infarct volumes (total infarct: male vs. female 46.6±7.2% vs. 43.2±9.3%, n=6/gp) and in Iba-1 staining of the ischemic brain were seen between male and female neonates. However, at 72 hours female neonates exhibited significantly smaller infarct size and improved behavior outcomes compared to males (total infarct: male vs. female 43.1±9.9% vs. 27.1±8.8%, n=6/gp, p <.05). Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at 72 hours. This male-specific phenotype was also seen at 7 days after injury. There was no difference in hormone levels at any of the three time points after stroke. Conclusions: Acute ischemia leads to an equivalent primary brain injury in male and female P10 mice. However, infarct damage worsens in males at sub-acute time points vs. females, as does the immune response. This sex difference independent of hormone levels exists in NAIS.

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Physical exercise as a human model of limited inflammatory response

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-040 ◽

1998 ◽

Vol 76 (5) ◽

pp. 589-597 ◽

Cited By ~ 53

Author(s):

Pang N Shek ◽

Roy J Shephard

Keyword(s):

Physical Exercise ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Active Phase ◽

Human Model ◽

Inflammatory Factors ◽

Trauma Patients ◽

Inflammatory Reactions ◽

Underlying Mechanisms

An inflammatory response represents a fundamental series of humoral and cellular reaction cascades in response to infection, tissue injury, and related insults. An excessive response is commonly seen under the pathological conditions of trauma, sepsis, and burns. It is becoming increasingly evident that most, if not all, of the distinguishing features of a classical inflammatory response are detectable in an exercising individual, namely mobilization and activation of granulocytes, lymphocytes, and monocytes; release of inflammatory factors and soluble mediators; involvement of active phase reactants; and activation of the complement and other reactive humoral cascade systems. While the manifestation of many exercise-induced immune and related changes has been reported and confirmed repeatedly, the underlying mechanisms triggering and modulating the elicited immune responses are, at best, poorly understood. Unlike the exaggerated and sometimes uncontrollable inflammatory response in septic and trauma patients resulting in morbidity and mortality, strenuous and severe exercise normally elicits an inflammatory response of a subclinical nature to facilitate the repairing process for site-specific tissue damage. Regardless of the inciting event, for example trauma, infection, or exercise, and given an appropriate triggering signal, a remarkably similar sequence of inflammatory reactions can be reproduced in the affected host. Therefore, physical exercise and training represent an acceptable and good model for the study of limited inflammatory responses in humans.Key words: trauma, infection, exercise, inflammatory response, cytokines.

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COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Cardiovascular Research ◽

10.1093/cvr/cvaa106 ◽

2020 ◽

Vol 116 (10) ◽

pp. 1666-1687 ◽

Cited By ~ 266

Author(s):

Tomasz J Guzik ◽

Saidi A Mohiddin ◽

Anthony Dimarco ◽

Vimal Patel ◽

Kostas Savvatis ◽

...

Keyword(s):

Cardiovascular System ◽

Troponin I ◽

Inflammatory Responses ◽

Myocardial Dysfunction ◽

Angiotensin Receptor Blockers ◽

Ventricular Tachyarrhythmia ◽

Cardiac Injury ◽

Fulminant Myocarditis ◽

Rapid Progression ◽

Cardiac Damage

Abstract The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

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Resolvin D1 and Resolvin D2 Protect Against Hypoxia/Reoxygenation Induced Lung and Kidney Damage in a Sickle Cell Mouse Model of Acute Vaso-Occlusive Crisis

Blood ◽

10.1182/blood.v126.23.966.966 ◽

2015 ◽

Vol 126 (23) ◽

pp. 966-966

Author(s):

Alessandro Mattè ◽

Antonio Recchiuti ◽

Charles Serhan ◽

Angela Siciliano ◽

Enrica Federti ◽

...

Keyword(s):

Sickle Cell ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Conflicts Of Interest ◽

Tissue Injury ◽

Hexaenoic Acid ◽

Glomerular Sclerosis ◽

Inflammatory Cell Infiltrate ◽

Activation Markers ◽

Hypoxia Reoxygenation

Abstract Sickle cell disease (SCD) is characterized by hemolytic anemia in association with acute and chronic life-threatening clinical complications. Acute vaso-occlusive crisis (VOCs) are the main cause of hospitalization for SCD patients. In VOCs, amplified inflammatory response plays a key role in acute organ damage. Pro-Resolving lipid mediators such as resolvins (Rv) accelerate resolution of acute inflammation in different models, indicating that stimulation of endogenous resolution of inflammatory processes may be an additional strategy in limiting tissue damage. Recent data suggest beneficial effects of Rvs in hypoxia/reoxygenation (H/R) related tissue injury. Here, we study the effects of Rvs on a model of acute VOCs using humanized SCD mice (Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow). We treated SCD and control healthy mice (AA, Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) (n =6-7 animals in each group) with RvD1, 7S, 8R, 17S- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid, 17R- RvD1, 7S, 8R, 17R- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid; RvD2, 7S, 16R, 17S-trihydroxy-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z-hexaenoic acid. Mice were treated with RvD1 and RvD2 at the dose of 2.5 ug/Kg by gavage 1 hour (hr) before H/R stress (10 hrs 8% oxygen followed by 3 hrs reoxygenation), which we have used in the past to mimic acute VOCs. We found that RvD1 and RvD2 significantly reduced the H/R-induced (i) increase in neutrophil count; (ii) lung inflammatory cell infiltrate, mucus and thrombi formation; (iii) glomerular inflammatory cell infiltration, glomerular sclerosis and thrombi formation. In the lung of H/R SCD mice, RvD1 prevented the H/R induced up-regulation of (i) cytokines such as MCP2, IL-6 and ET-1; (ii) vascular endothelial activation markers (VCAM-1 and ICAM-1; (iii) cytoprotective systems such as Prx6 and HO-1. In the kidney of H/R SCD mice, RvD1 significantly reduced H/R induced expression of IL-6 and ET-1 as well as HO-1. Our data indicate that RvD1 and RvD2 modulating inflammatory responses related to H/R in SCD, protect sickle cell target organs, and foster resolution. Thus, RvD1 and RvD2 might represent a novel therapeutic approach for acute VOCs in SCD. Disclosures No relevant conflicts of interest to declare.

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The host inflammatory responses, tumor stroma percentage, and survival in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.549 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 549-549

Author(s):

James Hugh Park ◽

Colin H. Richards ◽

Donald C. Mcmillan ◽

Paul G. Horgan ◽

Campbell S. D. Roxburgh

Keyword(s):

Colorectal Cancer ◽

Inflammatory Response ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Tumor Stroma ◽

Inflammatory Cell Infiltrate ◽

Cell Infiltrate ◽

Local Inflammatory Response ◽

Invasive Margin ◽

N Stage

549 Background: The role of host inflammatory responses in determining colorectal cancer (CRC) outcome is increasingly recognised. In particular, a marked local inflammatory response is associated with improved survival. However, determinants of this response are not clear. A plausible factor in the density, location and type of the inflammatory cell infiltrate is the extent of tumor stroma. The aim of the present study was to examine the relationship between tumor stroma percentage (TSP), tumor inflammatory infiltrate and survival in patients undergoing elective CRC resection. Methods: 335 patients who had undergone elective resection for stage I-III CRC at a single institution between 1997-2008 were included. TSP at the invasive margin (IM) was assessed on H and E sections and grouped as low (≤50%) or high (>50%). Local inflammatory response was assessed at the IM using Klintrup-Mäkinen (K-M) score and at the IM, tumor stroma and cancer cell nests (CCNs) using the following T-cell markers: CD3, CD8, CD45R0, FOXP3. Systemic inflammatory response was assessed using modified Glasgow Prognostic Score (mGPS). Results: Eighty-three patients (25%) had high TSP. High TSP was associated with increased T stage, N stage (both p < 0.01), margin and serosal involvement (both p < 0.05), an infiltrative invasive margin (p < 0.001) and tumor necrosis (p = 0.001). TSP was associated with decreased infiltration by CD3+ and CD8+ cells at the CCNs (p < 0.01 and p < 0.05 respectively) but not at the IM or stroma. K-M score showed a trend towards an inverse association with TSP (p = 0.067). CD45R0+ and FOXP3+cell infiltration and mGPS were not associated with TSP. On multivariate analysis, TSP was associated with poorer cancer-specific survival (HR 1.93, 95% CI 1.15-3.23, p = 0.012), independent of N stage, VI (both p < 0.05), low CD8 at the IM and CCNs (both p < 0.01) and mGPS (p = 0.001). Conclusions: TSP was associated with the presence of high risk pathological characteristics and down-regulation of host intra-tumoral immune responses and was independently associated with poorer cancer survival. The extent of tumor stroma is an important factor in the nature of the tumor inflammatory cell infiltrate and outcome in patients undergoing elective surgery for CRC.

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Estrogen accelerates heart regeneration by promoting the inflammatory response in zebrafish

Journal of Endocrinology ◽

10.1530/joe-19-0413 ◽

2020 ◽

Vol 245 (1) ◽

pp. 39-51 ◽

Cited By ~ 3

Author(s):

Shisan Xu ◽

Fangjing Xie ◽

Li Tian ◽

Samane Fallah ◽

Fatemeh Babaei ◽

...

Keyword(s):

Inflammatory Response ◽

Inflammatory Responses ◽

Cardiac Injury ◽

Specific Protein ◽

Sexual Differences ◽

Heart Regeneration ◽

Underlying Mechanisms ◽

Female Specific ◽

Estrogen Antagonist ◽

Zebrafish Heart

Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered pronounced immune and inflammatory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the zebrafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to cardiac injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provide a new model system for the study of sexual differences in human cardiac repair.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.727861 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhuqing Jin ◽

En Zheng ◽

Candice Sareli ◽

Pappachan E. Kolattukudy ◽

Jianli Niu

Keyword(s):

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Current Evidence ◽

Protective Mechanism ◽

Immune Functions ◽

Resolution Of Inflammation ◽

Knock Out ◽

The Stability

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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