Healing action of Interleukin-4 (IL-4) in acute and chronic inflammatory conditions: Mechanisms and therapeutic strategies

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 265, P. 108760 - 108760

Published: Nov. 28, 2024

Language: Английский

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Type 2 Innate Lymphoid Cell in Cardiovascular Diseases: Complexities and Potentials

Intensive Care Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Abstract Innate lymphoid cells (ILCs) are a class of lymphocytes that do not express specific antigen recognition receptors, which play significant role in various diseases due to their unique immunomodulatory functions. Among these, type 2 innate (ILC2s) form distinct subpopulation and recognized as key mediators anti-infective allergic responses. Cardiovascular leading cause intensive care unit admissions. diseases, including myocardial infarction heart failure, have complex pathogenesis involving inflammation, tissue injury, repair. Recent studies suggest ILC2s crucial cardiovascular by regulating promoting repair, facilitating cardiac remodeling through the secretion anti-inflammatory cytokines like IL-4, IL-5, IL-13, etc. However, health, potentially contributing adverse failure certain contexts. Thus, precise mechanisms influence disease processes remain incompletely understood. This review summarizes recent advances understanding ILC2 explores potential therapeutic targets, aiming identify new treatment strategies.

Language: Английский

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CD206 ⁺ IL-4Rα ⁺ Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy

Circulation, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

The role of cardiac CD (cluster differentiation) 206+ macrophages in chronic heart failure (HF) is unknown. We examined whether CD206+ expressing IL (interleukin)-4Rα are key drivers adverse left ventricular (LV) remodeling HF. Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce Macrophages murine and human hearts were profiled using flow cytometry immunostaining. In vivo myeloid-specific IL-4Rα deletion intramyocardial macrophage adoptive transfer defined the functional effects M[IL-4] macrophages. Antisense oligonucleotides used for gene silencing mice. steadily expanded after infarction, such that at 8 weeks they comprised ≈85% all These proliferative, predominantly CCR2- (C-C motif chemokine receptor) MHC (major histocompatibility complex) IIhi, correlated with LV dysfunction fibrosis. Nearly half expressed IL-4Rα, majority CD206+IL-4Rα+ coexpressed profibrotic FIZZ (found inflammatory zone) 1. IL-4-polarized bone marrow-derived also exhibited marked upregulation FIZZ1 induced FIZZ1-dependent myofibroblast differentiation both mesenchymal stem cells fibroblasts, part related DLL-4/Jagged1-Notch1 signaling cells. Intramyocardial M[IL-4], but not M[IL-10], naïve progressive over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, apoptosis. Myeloid-specific HF (initiated infarction) IL-4Rαf/fLysM-CreERT2 significantly reduced proliferation effectively depleted This was associated abrogation progression, reduction improved neovascularization. established reversed remodeling, improving neovascularization, dysfunction, suppressed local systemic inflammation. Last, alternatively activated CD163+ failing FIZZ3, homolog FIZZ1. Cardiac proliferate expand mediators pathological through secretion Inhibition alleviates ischemic cardiomyopathy.

Language: Английский

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Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans

AJP Heart and Circulatory Physiology, Journal Year: 2024, Volume and Issue: 326(5), P. H1080 - H1093

Published: March 1, 2024

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating progression. The literature suggests an important role for activation of interleukin-13 interleukin-4 signaling improving ischemic outcomes after myocardial infarction mice. Dupilumab, neutralizing antibody that inhibits shared IL13/IL4 receptor subunit IL4Rα, widely used conditions such as ectopic dermatitis humans. If global depletion IL4Rα influences failure, either mice humans taking dupilumab, unknown. Here, we investigated pathophysiological effects genetic deletion adult surgically induced (MI). We also determined risk patients with concomitant usage dupilumab using collaborative patient data network TriNetX. Global results exacerbated cardiac dysfunction associated reduced capillary size In agreement our findings mice, treatment significantly increased development preexisting diagnosis disease. Our indicate systemic protective against human specifically following event. Thus, compelling evidence presented hereby advocates randomized clinical trial investigating ischemia another underlying condition.

Language: Английский

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Emerging Anti-Inflammatory COPD Treatments: Potential Cardiovascular Impacts

International Journal of COPD, Journal Year: 2024, Volume and Issue: Volume 19, P. 2481 - 2495

Published: Nov. 1, 2024

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition often complicated by cardiovascular (CVD) due to shared pathways. This review explores the impacts of emerging anti-inflammatory therapies in COPD. Phosphodiesterase (PDE) inhibitors may offer effects with improved lung function but pose potential risks for arrhythmias when PDE3 inhibited although PDE4 reduce events improving endothelial and reducing thrombosis. Similarly, p38 mitogen-activated protein kinase (MAPK) phosphoinositide 3-kinase (PI3K) target COPD-related inflammation benefit COPD patients CVD. MAPK cardiac fibrosis, enhance contractility lower risk arrhythmia. PI3K PI3K/Akt pathway, which drives atherosclerosis thus potentially mitigate both plaque instability fibrosis. Biologic therapies, including monoclonal antibodies that inhibit IL-5, IL-13/IL-4, thymic stromal lymphopoietin, IL-33, IL-17A, show promise exacerbations require close monitoring their immunomodulatory effects. Single-target neutrophil elastase or matrix metalloproteinases limited efficacy aid stabilizing atherosclerotic plaques through promoting vascular smooth muscle cell proliferation. However, tendency degrade extracellular attract immune cells heighten rupture risk, contraindicating use Alpha-1 antitrypsin replacement therapy holds promise, providing protection, especially myocardial injury. Understanding influence these innovative on CVD vital, making it imperative examine molecules at an early stage.

Language: Английский

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SPECT Imaging of Cardiac Inflammation by Targeting IL4 Receptor-α on Macrophages

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

The inflammation response is a prominent sign of myocardial infarction (MI), mediating the process cardiac fibrosis and ventricular remodeling. Inflammation visualization holds new promise for guiding anti-inflammatory therapy. Interleukin-4 receptor α (IL4Rα) interacts with IL4, closely related to macrophage polarization. This study aimed evaluate feasibility technetium-99m (99mTc) labeled IL4Rα antibody probe ([99mTc]Tc-HYNIC-CM310) targeting postinfarction SPECT imaging. [99mTc]Tc-HYNIC-CM310 was prepared by radiolabeling an IL4Rα-specific monoclonal (CM310) 99mTc. Images were acquired at 0.5, 6, 12, 24, 36 h postinjection on next day after MI sham model preparation, biodistribution performed h. mean percentage injected dose per gram (%ID/g) various tissues obtained drawing regions interest. [18F]FDG metabolism imaging comparison verification. Immunofluorescence costaining flow cytometry conducted validate coexpression macrophages. yield approximately 88.31% ± 1.70%, radiochemical purity 93.70% 0.38%. accumulation in infarcted myocardium increased starting 12 postinjection. tracer uptake significantly higher than same site sham-operated rats (P < 0.05). region consistent metabolic defect inflammatory seen PET. staining confirmed colocalization IL4Rα+ cells markers myocardium. We successfully validated precise macrophages, offering opportunity treatment inflammation.

Language: Английский

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Polarized macrophages modulate cardiac structure and contractility under hypoxia in novel immuno-heart on a chip

APL Bioengineering, Journal Year: 2025, Volume and Issue: 9(2)

Published: May 1, 2025

Cardiac adaptation to hypoxic injury is regulated by dynamic interactions between cardiomyocytes and macrophages, yet the impacts of immune phenotypes on cardiac structure contractility remain poorly understood. To address this, we developed immuno-heart a chip, novel in vitro platform investigate cardiomyocyte–macrophage under normoxic conditions. By integrating neonatal rat ventricular myocytes (NRVMs) bone marrow-derived macrophages—polarized pro-inflammatory (M1) or pro-healing (M2/M2*) phenotypes—we elucidated dual protective detrimental roles macrophages play modulating cardiomyocyte cytoskeletal architecture contractility. Pro-inflammatory stimulation reduced structural metrics (z-line length, fraction, integrity) co-cultures. Under hypoxia, M1-stimulated NRVM monocultures exhibited declines organization—quantified actin z-line orientational order parameters. Relative monocultures, co-cultures attenuated hypoxia-induced active stress but produced weaker stresses. In contrast, improved preserved post-hypoxia organization Notably, M2-stimulated restored systolic stress, albeit with increased diastolic stress. RNAseq analysis identified upregulated pathways driving these changes. Cytokine profiles revealed stimulation-specific density-dependent tumor necrosis factor-alpha interleukin-10 secretion patterns. Together, findings quantitatively link clinically relevant macrophage cytokines distinct changes contractility, offering mechanistic insights into modulation dysfunction. Moreover, chip represents an innovative framework guide development future therapies that integrate targets enhance patient outcomes.

Language: Английский

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IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages

JCI Insight, Journal Year: 2023, Volume and Issue: 9(2)

Published: Dec. 5, 2023

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 neonatal heart regeneration; however, the cell types mediating regeneration and extent of adult injury are unknown. We identified an abundant source related cytokine, IL-4, type 2 innate lymphoid cells, but this phenomenon declined precipitously hearts. Moreover, receptor deletion macrophages impaired function resulted larger scars early MI. By using combination recombinant administration cell-specific genetic models, we found specifically to mediated functional recovery MI mice. Single transcriptomics revealed subpopulation response administration. These IL-13-induced were highly efferocytotic by high IL-1R2 expression. Collectively, elucidated strongly proreparative directly following injury. While pathway active proregenerative stages, reactivation macrophage required adults.

Language: Английский

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IL-4 attenuates myocardial infarction injury by promoting M2 macrophage polarization

Annals of Medicine and Surgery, Journal Year: 2024, Volume and Issue: unknown

Published: April 19, 2024

IL-4, an immunoregulatory cytokine, plays a role in various cellular pathways and is known to regulate M2 macrophage polarization. Numerous studies have suggested that promoting the polarization of macrophages toward phenotype beneficial for myocardial infarction (MI) recovery. However, whether IL-4 can achieve therapeutic effects MI by regulating remains unclear. In this study, we observed increased proportion ischemic myocardium compared PBS group. Additionally, reduced infiltration inflammatory cells expression proinflammatory-related proteins, while enhancing genes associated with tissue repair. Furthermore, facilitated recovery cardiac function fibrosis post-MI phase. Importantly, when were depleted, benefits mentioned above attenuated. These findings provide evidence effectiveness treating through regulation polarization, thereby encouraging further development approach.

Language: Английский

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The Influence of Comorbidities on Chemokine and Cytokine Profile in Obstructive Sleep Apnea Patients: Preliminary Results

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(3), P. 801 - 801

Published: Jan. 19, 2023

Obstructive sleep apnea (OSA) is frequently associated with a chronic inflammatory state and cardiovascular/metabolic complications. The aim of this study was to evaluate the influence certain comorbidities on panel 45 chemokines cytokines in OSA patients special regard their possible association cardiovascular diseases.This cross-sectional performed 61 newly diagnosed patients. For measurement plasma concentration cytokines, magnetic bead-based multiplex assay for Luminex® platform used.In concomitant COPD, there were increased levels pro-inflammatory (CCL11, CD-40 ligand) decreased anti-inflammatory cytokine (IL-10), while diabetes, (IL-6, TRIAL). Obesity both (IL-13) (IL-1RA) cytokines. Hypertension (CCL3) (IL-10) Increased daytime pCO2, low mean nocturnal SaO2, oxygen desaturation index (CXCL1, PDGF-AB, TNF-α, IL-15).In diabetes elevated may favor persistence further consequences. Nocturnal hypoxemia, frequent episodes desaturation, pCO2 are factors contributing

Language: Английский

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