Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

Jiang, Yi; Bai, Jianwen; Tang, Lunxian; Zhang, Pei; Pu, Jun

doi:10.1159/000430224

Cited by 22 publications

(13 citation statements)

References 53 publications

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“…Therefore, inhibitors of MMP-9 production from macrophages may be useful to prevent plaque rupture. Furthermore, MMP-9 deletion was proved to improve left ventricular function in remodeling myocardium post-MI [43]. In this study, we found that green tea polyphenol EGCG significantly inhibited the expression and activity of MMP-9 in a concentration-dependent manner in PMA-induced macrophages.…”

Section: Discussionmentioning

confidence: 55%

Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages

Wang

et al. 2016

Cell Physiol Biochem

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Background/Aims: It is well documented that overexpression of EMMPRIN (extracellular matrix metalloproteinase inducer) and MMPs (matrix metalloproteinases) by monocytes/macrophages plays an important role in atherosclerotic plaque rupture. Green tea polyphenol epigallocatechin-3-gallate (EGCG) has a variety of pharmacological properties and exerts cardiovascular protective effects. Recently, the 67-kD laminin receptor (67LR) has been identified as a cell surface receptor of EGCG. The aim of the present study was to evaluate the effects of EGCG on the expression of EMMPRIN and MMP-9 in PMA-induced macrophages, and the potential mechanisms underlying its effects. Methods: Human monocytic THP-1 cells were induced to differentiate into macrophages with phorbol 12-myristate 13-acetate (PMA). Protein expression and MMP-9 activity were assayed by Western blot and Gelatin zymography, respectively. Real-time PCR was used to examine EMMPRIN and MMP-9 mRNA expression. Results: We showed that EGCG (10-50µmol/L) significantly inhibited the expression of EMMPRIN and MMP-9 and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and c-Jun N-terminal kinase (JNK) in PMA-induced macrophages. Downregulation of EMMPRIN by gene silencing hindered PMA-induced MMP-9 secretion and expression, indicating an important role of EMMPRIN in the inhibition of MMP-9 by EGCG. Moreover, 67LR was involved in EGCG-mediated suppression of EMMPRIN and MMP-9 expression. Anti-67LR antibody treatment led to abrogation of the inhibitory action of EGCG on the expression of EMMPRIN and MMP-9 and activation of ERK1/2, p38, and JNK. Conclusion: Our results indicate that EGCG restrains EMMPRIN and MMP-9 expression via 67LR in PMA-induced macrophages, which also suggests that EGCG may be a possible therapeutic agent for stabilizing atherosclerotic plaque.

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Section: Discussionmentioning

confidence: 55%

Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages

Wang

et al. 2016

Cell Physiol Biochem

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“…6 Studies in animals reported that the inhibition of the reparative process can reduce the infarct size and improve the evolution of the VR. 44,45 However, the early use of anti-inflammatory drugs after infarction promoted the thinning and expansion of the infarct zone in animals and increased the incidence of cardiac rupture in patients. 46 Thus, a defect in the healing process or an increase in the infarct size and parietal stress were the main determinants of the expansion and the appearance of adverse clinical events, heart failure, and death.…”

Section: Galectin-3 On Healing and Remodelingmentioning

confidence: 99%

Genetic Deletion of Galectin-3 Alters the Temporal Evolution of Macrophage Infiltration and Healing Affecting the Cardiac Remodeling and Function after Myocardial Infarction in Mice

Cassaglia

Penas

Betazza

et al. 2020

The American Journal of Pathology

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We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3 -/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80þ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-a, transforming growth factor-b, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.

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“…Macrophages in an injured spinal cord have dynamic phenotypes and functions that can change based on the spinal lesion microenvironment (Stout and Suttles, 2004; Menzies et al, 2010). CCL21 and its receptor CCR7 are widely expressed in T cells, dendritic cells, fibroblasts, smooth muscle, and intravascular cells, and CCL21 contributes to inflammation and remodeling of the extracellular matrix (Jiang et al, 2015). CCR7 has an important role to migrate dendritic cells and/or T cells from brain parenchyma to deep cervical lymph nodes for immune response; CCR7 deficient inflammatory cells are retained in the central nervous system (CNS) and exacerbate CNS autoimmune diseases, including multiple sclerosis (Kivisäkk et al, 2004; Clarkson et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout (plt) Mouse

Honjoh

Nakajima

Hirai

et al. 2019

Front. Cell. Neurosci.

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Spinal cord injury (SCI) causes loss of normal sensation and often leads to debilitating neuropathic pain (NeP). Chronic NeP develops at or below the SCI lesion in as many as 80% of patients with SCI and may be induced by modulators of neuronal excitability released from activated microglia and macrophages. In the inflammatory response after SCI, different microglia/macrophage populations that are classically activated (M1 phenotype) or alternatively activated (M2 phenotype) have become of great interest. Chemokines have also recently attracted attention in neuron-microglia communication. CCL21 is a chemokine that activates microglia in the central nervous system (CNS) and is expressed only in neurons with an insult or mechanical injury. In this study using an SCI model in mutant (plt) mice with deficient CCL21 expression, we assessed post-SCI NeP and expression of microglia/macrophages and inflammatory cytokines at the injured site and lumbar enlargement. SCI-induced hypersensitivities to mechanical and thermal stimulation were relieved in plt mice compared with those in wild-type (C57BL/6) mice, although there was no difference in motor function. Immunohistochemistry and flow cytometry analysis showed that the phenotype of microglia/macrophages was M1 type-dominant in both types of mice at the lesion site and lumbar enlargement. A decrease of M1-type microglia/macrophages was seen in plt mice compared with wild-type, while the number of M2-type microglia/macrophages did not differ between these mice. In immunoblot analysis, expression of M1-induced cytokines [tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ)] was decreased in plt mice, while that of M2-induced cytokines interleukin-4 (IL-4, IL-10) did not differ in the two types of mice. The results of this study indicate that suppression of expression of inflammatory cytokines by decreasing the number of M1-type microglia/macrophages at the injured site and lumbar enlargement is associated with provision of an environment for reduction of NeP. These findings may be useful for the design of new therapies to alleviate NeP after SCI.

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Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

Cited by 22 publications

References 53 publications

Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages

Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages

Genetic Deletion of Galectin-3 Alters the Temporal Evolution of Macrophage Infiltration and Healing Affecting the Cardiac Remodeling and Function after Myocardial Infarction in Mice

Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout (plt) Mouse

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