Table 1.
Selected published articles related to the myocardial fibrosis regulated by macrophages
| Study | Macrophage phenotype | Model | Main intervention | Effect of intervention on fibrosis | Effect of intervention on prognosis | Conclusion | Citation |
|---|---|---|---|---|---|---|---|
| Acute myocardial infarction acute phase | |||||||
| Ducharme et al. (2000) | CD11b+ | Permanent coronary artery ligation | Mmp9−/− | Inhibit | Improve | MMP-9 promotes macrophage recruitment into the heart and regulates the levels of other MMPs, which facilitates left ventricular dilation and collagen deposition after MI. | 78 |
| Hwang et al. (2001) | CD11b+ | Permanent coronary artery ligation | IL-1β antibody treatment | Inhibit | Deteriorate | Administration of anti-IL-1β neutralizing antibodies during the acute phase of MI is harmful, leading to reduced collagen accumulation in the infarct area and promoting ventricular rupture and dilation. In the chronic phase of MI, anti-IL-1β antibodies inhibit collagen deposition in non-infarcted areas and reduce interstitial fibrosis. | 578 |
| Bujak et al. (2008) | CD11b+ | Transient coronary artery ligation | Il1r1−/− | Inhibit | Improve | IL-1 signaling promotes the infiltration of neutrophils and macrophages into the infarcted myocardium and the expression of MMP-2, MMP-3, and TGF-β in the peri-infarct area through IL-1R1, thereby promoting inflammation and collagen deposition. | 65 |
| Howangyin et al. (2016) | F4/80+ | Permanent coronary artery ligation |
1. Mertk−/−/ Mfge8−/− 2. LysM-Cre+/ Vegfafl/fl |
Both promote | Both deteriorate | Macrophages expressing Mertk and Mfge8 participate in the clearance of damaged tissue after MI. The endocytosis of damaged tissue promotes macrophage M2 polarization and secretes VEGFA to regulate neovascularization and collagen deposition. | 84 |
| Wang et al. (2017) | CD68+ | Permanent coronary artery ligation | MiR-155−/− | Promote | Improve | Macrophage-derived miR-155 promotes fibroblast-mediated inflammation by reducing Socs1 expression and inhibits cardiac fibroblast proliferation by reducing Sos1 expression. | 588 |
| Bageghni et al. (2019) | CD11b+ | Permanent coronary artery ligation | Col1a2-CreERT/ Il1r1fl/– | Inhibit | Improve | Specific knockdown of IL-1R1 on fibroblasts reduces the expression of cardiac remodeling markers and collagen deposition. | 70 |
| Jing et al. (2019) | CD11b+ | Permanent coronary artery ligation | Il6−/− | Inhibit | Improve | IL-6 may promote collagen production by promoting the expression of TNF-α and inhibiting M2 macrophage activation. | 73 |
| Kubota et al. (2019) | Ly6Clow | Permanent coronary artery ligation | Mmp12−/− | Inhibit | Deteriorate | MMP-12 produced by Ly6Clow macrophages prevents neutrophil infiltration by inhibiting the CXCL1/CXCL2/CXCL5-CXCR2 axis, thereby significantly reducing MMP-9 secretion and increasing collagen deposition. | 81 |
| Razin et al. (2021) | CD11b+ | Permanent coronary artery ligation | Il1a−/− | Promote | Deteriorate | IL-1α stimulates fibroblasts to express StAR, thereby inhibiting fibroblast apoptosis during the inflammatory phase, which may be beneficial for inhibiting fibrosis. | 589 |
| Lugrin et al. (2023) | CD11b+ | Permanent coronary artery ligation | Il1a−/− | Inhibit | Improve | IL-1α promotes the release of pro-inflammatory mediators such as IL-6 and MCP-1 and the expression of fibrotic genes such as CTGF, thereby promoting myocardial fibrosis. | 75 |
| Acute myocardial infarction reparative phase | |||||||
| Bujak et al. (2007) | F4/80+ | Permanent coronary artery ligation | Smad3−/− | Inhibit | Improve | Smad3 does not alter the time course of resolution of inflammation in healing infarcts but can promote interstitial fibrosis in non-infarcted myocardium to worsen cardiac function. | 103 |
| Krishnamurthy et al. (2007) | CD68+ | Permanent coronary artery ligation |
1. Recombinant IL-10 treatment 2. HuR knockdown by siRNA |
Both inhibit | Both improve | IL-10 inhibits fibrosis by inhibiting the HuR/MMP-9 axis. | 112 |
| Dobaczewski et al. (2010) | F4/80+ | Transient coronary artery ligation | Smad3−/− | Inhibit | NA | Knocking out Smad3 inhibits fibrosis mediated by TGF-β1 and CTGF, which results in an increase in the number but functional defects of fibroblasts, thereby reducing collagen deposition. | 101 |
| Shirakawa et al. (2018) | Galectin-3high CD206+ | Permanent coronary artery ligation | Spp1−/− | Inhibit | Deteriorate | After MI, the IL-10-STAT3-Galectin-3 axis is important for macrophage M2 polarization and production of the profibrotic substance OPN, and OPN is almost produced by Galectin-3high CD206+ macrophages. | 110 |
| Chen et al. (2019) | LyzM+ | Permanent coronary artery ligation | LyzM-Cre+/ Smad3fl/fl | No significant change | Deteriorate | After MI, Smad3 in macrophages can mediate the acquisition of phagocytic phenotype and promote an anti-inflammatory transition, but it has no significant effect on myofibroblast density or collagen content. | 108 |
| Shirakawa et al. (2020) | Galectin-3high CD206+ | Permanent coronary artery ligation | M-CSF activator treatment | Promote | Improve | IL-10 and M-CSF synergistically activate STAT3 and ERK in cardiac macrophages to upregulate the expression of Galectin-3 and MerTK, leading to the functional maturation of cardiac macrophages and the production of profibrotic substance OPN. | 109 |
| Alonso-Herranz et al. (2020) | Lyz2+ | Transient and permanent coronary artery ligation | Lyz2-Cre+/ Mmp14fl/fl | Inhibit | Improve | Macrophages promote endothelial-mesenchymal transition through MMP-14/TGF-β1/Smad2 after MI, leading to myocardial fibrosis. | 93 |
| Chen et al. (2022) | LyzM+ | Permanent coronary artery ligation | LyzM-Cre+/ Smad2fl/fl | No significant change | No significant change | Smad2 in bone marrow cells has no significant effect on the clearance of infarcted cells, inflammation or fibrosis in the infarcted heart. | 105 |
| Humeres et al. (2022) | F4/80+ | Permanent coronary artery ligation | Postn-Cre+/ Smad7fl/fl | Promote | Deteriorate | The TGF-β-driven myofibroblast activation is regulated by negative feedback from Smad7 through inhibition of Smad2/3, ERK, AKT, and EGFR signaling. | 590 |
| Garlapati et al. (2023) | CCR2+ | Permanent coronary artery ligation |
1. LysM-Cre+/ F2rl1fl/fl 2. LysM-Cre+/ F3fl/fl |
Both inhibit | Both improve | TF-PAR2 signaling activates NOX2/ERK-dependent TGF-β1 production in myeloid cells and activates the TGF-β1/SMAD2 pathway to promote fibrosis. | 95 |
| Wang et al. (2023) | CD206+ | Permanent coronary artery ligation | Vsig4−/− | Inhibit | Deteriorate | Hypoxia induces the expression of VSIG4 in macrophages, which promotes the expression of TGF-β1 and IL-10, leading to the transformation of fibroblasts into myofibroblasts. | 94 |
| Chronic myocardial infarction | |||||||
| Yan et al. (2012) | CD11b+ | Permanent coronary artery ligation |
1. Il17a−/− 2. Il23a−/− 3. Tcrγδ−/− 4. Tlr2−/− 5. Tlr4−/− 6. Tlr2−/−/ Tlr4−/− |
All inhibit | All improve | TLR signaling regulates M1 macrophages to produce IL-1β and IL-23, which drive cardiac γδ T cell expansion and production of IL-17A. In the late stage of myocardial injury, IL-17A continues to promote the production of pro-inflammatory cytokines, MMPs, and TGF-β, stimulating fibroblast proliferation and collagen deposition. | 130 |
| Ismahil et al. (2014) | CCR2+ | Permanent coronary artery ligation |
1. Splenectomy 2. Splenocytes adoptively transferred |
1. NA 2. Promote |
1. Promote 2. Deteriorate |
Spleen-derived proinflammatory macrophages and monocytes are increased in failing hearts, and they induce cardiac inflammation and fibrosis. | 118 |
| Ischemia reperfusion | |||||||
| Huebener et al. (2008) | CCR2+ | Transient coronary artery ligation | Cd44−/− | Inhibit | Deteriorate | After IR, CD44 expression is markedly induced in macrophages, and it increases collagen deposition by inhibiting post-infarction inflammatory response, stimulating the TGF-β signaling pathway, and promoting fibroblast infiltration and proliferation. | 139 |
| Fan et al. (2009) | F4/80+ | Transient coronary artery ligation | Clec7a−/− | Inhibit | Improve | Dectin-1 induces macrophage M1 polarization and releases pro-inflammatory cytokines TNF-α, IL-1β, and IL-23. Dectin-1 also promotes the expression of CXCL1 and G-CSF in macrophages to mediate neutrophil infiltration, enhance early inflammatory response, and ultimately lead to more severe fibrosis. | 137 |
| Feng et al. (2022) | CCR2+ | Transient coronary artery ligation | Ccl17−/− | Inhibit | Improve | CCL17 is expressed in CCR2+ macrophages and inhibits Tregs recruitment which can suppress macrophage-associated inflammation, promoting inflammation and fibrosis. | 138 |
| Li et al. (2023) | ARG-1+ | Transient coronary artery ligation | M2-derived sEV treatment | Inhibit | Improve | sEV derived from M2 macrophages can regulate the glucose uptake and glycolysis levels of CCR2+ macrophages to reduce the production of mitochondrial reactive oxygen species, inducing the transformation of macrophages into a repair phenotype and ultimately promoting left ventricular fibrosis. | 142 |
| Pressure overload | |||||||
| Ma et al. (2012) | F4/80+ | Ang-II infusion | Il6−/− | Inhibit | NA | Macrophages stimulate cardiac fibroblasts to produce IL-6, which induces TGF-β1 production and Smad3 phosphorylation in cardiac fibroblasts, thereby stimulating myocardial fibrosis. | 184 |
| Verma et al. (2012) | F4/80+ | ISO infusion |
1. Il10−/− 2. Recombinant IL-10 treatment |
1. Promote 2. Inhibit |
1. Deteriorate 2. Improve |
IL-10 inhibits the NF-κB pathway through STAT3, thereby reducing isoproterenol-induced myocardial fibrosis. | 591 |
| Shimojo et al. (2015) | CCR2+ | Ang-II infusion | Tnc−/− | Inhibit | NA | Tenascin-C accelerates the migration of macrophages and the expression of pro-inflammatory cytokines through the integrin αVβ3/NF-κB/interleukin-6 axis, thereby promoting the collagen secretion of cardiac fibroblasts. | 592 |
| Verma et al. (2017) | F4/80+ | TAC | Il10−/− | Promote | Improve | IL-10 inhibits TGF-β-Smad-miR-21-mediated activation of bone marrow fibroblasts, thereby inhibiting fibrosis. | 174 |
| Khalil et al. (2017) | F4/80+ | TAC |
1. Postn-Cre+/ Tgfbr1/2fl/fl 2. Postn-Cre+/ Smad2fl/fl 3. Postn-Cre+/ Smad3fl/fl 4. Postn-Cre+/ Smad2/3fl/fl |
1. Inhibit 2. No significant change 3. Inhibit 4. Inhibit |
All improve | TGF-β-Smad2/3 signaling in cardiac fibroblasts promotes fibroblast differentiation and proliferation to facilitate the fibrotic response induced by pressure overload. | 593 |
| Suetomi et al. (2018) | F4/80+ | TAC |
1. MLC2v-Cre+/ Camk2dfl/fl 2. α-MHC-Cre+/ Ccl2fl/fl |
Both inhibit | Both improve | CaMKIIδ activates the NF-κB pathway in cardiomyocytes, which activates the inflammasome and expresses inflammatory genes such as MCP-1 and IL-1β, leading to the recruitment of macrophages and ultimately fibrosis. | 594 |
| Chou et al. (2018) | CD11b+ | Aldosterone infusion |
1. MR inhibitor treatment 2. PI3K / Akt inhibitor treatment 3. MAPK / ERK inhibitor treatment 4. MAPK / p38 inhibitor treatment 5. IL-6 inhibitor treatment |
All inhibit | NA | Aldosterone induces endothelial cells to produce IL-6 through the MR/PI3K/Akt/NF-κB pathway, and IL-6 promotes collagen secretion by fibroblasts through IL-6 trans-signaling. | 185 |
| Hulsmans et al. (2018) | CX3CR1+ | Aldosterone infusion | Cx3cr1-Cre+/ Il10fl/fl | Inhibit | Improve | IL-10 produced by cardiac macrophages promotes the conversion of macrophages into MHC-IIhigh macrophages and the expression of more OPN and TGF-β and fewer MMPs, thereby promoting collagen deposition. | 170 |
| Abe et al. (2019) | Ly6Chigh | TAC |
1. LysM-Cre+/ Hif1afl/fl 2. Col1a1-Cre+/Osmrfl/fl |
Both promote | Both deteriorate | Ly6Chigh macrophages accumulate in myocardial hypoxic areas in a HIF-1α-dependent manner and secrete oncostatin-m to directly inhibit TGF-β-mediated fibroblast activation. | 190 |
| Liao et al. (2020) | CD11b+ | Aldosterone infusion | IL-6 antibody treatment | Inhibit | NA | Aldosterone promotes macrophage infiltration through the MR/IL-6/JAK/COX-2/PGE2 pathway, thereby promoting fibrosis. | 159 |
| Lv et al. (2021) | F4/80+ | TAC | NLRP3 inhibitor treatment | Inhibit | Improve | NLRP3 promotes myocardial fibrosis by promoting macrophage infiltration and activating the TGF-β/Smad4 pathway. | 153 |
| Chen et al. (2022) | Ly6Chigh | Ang-II infusion | LysM-Cre+/ Wwp2fl/fl | Inhibit | Improve | The interaction of WWP2 with transcription factor IRF7 in macrophages can drive downstream CCL5 and IFN signaling to promote the infiltration of Ly6Chigh monocytes and the expression of pro-inflammatory genes, thereby promoting myofibroblast activation. | 167 |
| Yu et al. (2023) | LysM+ | TAC | LysM-Cre+/ Nlrc5fl/fl | Promote | Deteriorate | NLRC5 interacts with HSPA8 in cardiac macrophages to inhibit the NF-κB pathway and IL-6 secretion, thereby inhibiting cardiac fibroblast activation. | 169 |
| Ye et al. (2023) | F4/80+ | Ang-II infusion | Clec7a−/− | Inhibit | Improve | Ang-II acts on Dectin-1 to activate the Syk/NF-κB signaling pathway and induce the expression of pro-inflammatory cytokines in macrophages, thereby activating fibroblasts. | 157 |
| Myocarditis | |||||||
| Szalay et al. (2009) | Mac-3+ | CVB3 infection | Vitamin D analog treatment | Inhibit | Improve | Calcitriol produced by vitamin D metabolism activates vitamin D signaling in macrophages, increases the expression of pERK in macrophages, and stimulates the production of pro-fibrotic substances such as OPN and TGF-β1. | 210 |
| Gruhle et al. (2012) | CCR2+ | CVB3 infection | Iloprost treatment | Promote | Deteriorate | Infiltrating macrophages express iNOS to stimulate p44/42 MAPK activation, which promotes macrophages to secrete CTGF, ultimately leading to increased fibrosis. | 209 |
| Kraft et al. (2019) | Mac-3+ | CVB3 infection | IL-1β antibody treatment | Inhibit | NA | The virus induces macrophages to secrete IL-1, which may stimulate an elevation in circulating levels of IL-6, thereby facilitating myocardial fibrosis. | 208 |
| Dilated cardiomyopathy | |||||||
| Psarras et al. (2012) | CD11+ | Desmin knockout | Spp1−/− | Inhibit | Improve | Infiltrating macrophages are the main source of OPN, and OPN can promote the secretion of Galectin-3 to promote fibrosis. | 220 |
| Touvron et al. (2012) | CCR2- | Cardiac-specific SRF knockout | Cardiomyocyte-specific IGF-1 overexpression | Inhibit | Improve | IGF-1 prevents fibroblast proliferation and myocardial fibrosis by inhibiting CTGF. | 223 |
| Zhang et al. (2021) | F4/80+ | DOX infusion | NLRP3 inhibitor treatment | Inhibit | Improve | NLRP3 inflammasome promotes the activation of ASC, caspase-1, IL-18, IL-1β, and GSDMD, thereby promoting inflammation and myocardial fibrosis. | 218 |
| Liu et al. (2022) | CCR2+ CD206+ | DOX infusion | M2-like macrophages infusion | Inhibit | Improve | Adoptive transfer of M2-like macrophages attenuates doxorubicin-induced myocardial fibrosis by transferring mitochondria from macrophages into injured cardiomyocytes. | 32 |
| Diabetic cardiomyopathy | |||||||
| Qi et al. (2014) | F4/80+ | Ang-II infusion | Adipoq−/− | Promote | Deteriorate | APN level is significantly reduced in diabetes, which reduces macrophage autophagy and increases the secretion of inflammatory cytokines, thereby promoting myocardial fibrosis. | 243 |
| Govindappa et al. (2020) | CCR2+ | Obese receptor knockout | Bone marrow-derived macrophages-exosomes with HuR deficiency | Inhibit | Improve | Exosome-associated HuR from bone marrow-derived macrophages is transferred to fibroblasts and induces inflammatory and fibrotic responses in fibroblasts. | 240 |
| Widiapradja et al. (2021) | Galectin-3+ CD86+ | Obese receptor knockout | SP treatment | Inhibit | Improve | Reduced SP in diabetic hearts significantly increases M1/M2 ratio, leading to the occurrence of fibrosis. | 239 |
| Wu et al. (2022) | Galectin-3+ CD86+ | Streptozotocin-induced and intermittent high-glucose infusion | SGLT1 knockdown by shRNA | Inhibit | Improve | Glycemic variability promotes macrophages polarization toward M1 by acting on SGLT-1, thereby aggravating myocardial fibrosis. | 238 |
| Zhu et al. (2022) | CD68+ | Streptozotocin-induced | Galectin-3 knockdown by shRNA | Inhibit | Improve | High glucose induces an increase in Galectin-3 in macrophages. Galectin-3 secretes pro-inflammatory cytokines by activating NF-κB to promote myocardial fibrosis. | 237 |
| Yang et al. (2023) | F4/80+ | Streptozotocin-induced | Clec7a−/− | Inhibit | Improve | High glucose increases the expression of macrophage pattern recognition receptor Dectin-1. Dectin-1 secretes pro-inflammatory cytokines by activating NF-κB and promotes myocardial fibrosis. | 236 |
| Cardiac aging | |||||||
| Trial et al. (2017) | CD36+ | Natural aging | Ccl2−/− | Inhibit | Improve | Fibroblasts in the aging heart highly express MCP-1 in response to ROS. MCP-1 induces monocyte infiltration and polarization into alternatively activated M2a macrophages, thereby promoting fibrosis. | 250 |
| Toba et al. (2017) | F4/80+ | Natural aging | Macrophage-specific Mmp9 overexpression | Inhibit | Deteriorate | With age, overexpression of macrophage-derived MMP-9 leads to insufficient angiogenesis and then triggers myocardial inflammatory response, which induces the production of fibrotic cytokines and promotes the accumulation of collagen. | 255 |
| Cieslik et al. (2017) | CD36+ | Natural aging | AMPK activator treatment | Inhibit | Improve | The Erk pathway is activated in fibroblasts in the aging heart to promote MCP-1 secretion. MCP-1 then mediates monocyte infiltration and polarization into M2a macrophages, promoting myocardial fibrosis. | 251 |
TGF transforming growth factor, Mertk Mer tyrosine kinase, Mfge8 Milk fat globule epidermal growth factor 8, VEGFA vascular endothelial growth factor A, Socs1 suppressor of cytokine signaling 1, Sos1 son of sevenless homolog 1, Ly6C lymphocyte antigen 6 complex, locus C, StAR steroidogenic acute regulatory protein, CTGF connective tissue growth factor, Smad small mothers against decapentaplegic, HuR human antigen R, NA not applicable, OPN osteopontin, STAT3 signal transducers and activators of transduction 3, LyzM lysozyme M, M-CSF macrophage colony-stimulating factor, ERK extracellular signal-regulated kinase, Lyz2 lysozyme M, EGFR epidermal growth factor receptor, TF tissue factor, PAR2 protease-activated receptor 2, NOX2 NADPH oxidase 2, VSIG4 V-set and Ig domain-containing 4, Dectin-1 dendritic cell-associated C-type lectin-1, G-CSF granulocyte colony-stimulating factor, sEV small extracellular vesicles, TLR toll-like receptor, ISO isoproterenol, TAC transverse aortic constriction, CaMKIIδ Calcium/calmodulin dependent protein kinase IIδ, MR Mineralocorticoid receptor, PI3K Phosphatidylinositol-3-kinase, MAPK Mitogen-activated protein kinase, HIF-1α hypoxia-inducible Factor-1α, JAK Janus kinase, COX-2 cyclooxygenases-2, NLRP3 NOD-like receptor thermal protein domain associated protein 3, WWP2 WW domain-containing protein 2, IRF7 interferon regulatory factor 7, IFN interferon, NLRC5 NLR family CARD domain containing 5, HSPA8 heat shock protein family A member 8, Syk Spleen tyrosine kinase, CVB3 Coxsackievirus B3, iNOS Inducible nitric oxide synthase, SRF Serum response factor, IGF-1 Insulin-like growth factor 1, DOX doxorubicin, ASC apoptosis-associated speck-like protein containing a caspase recruitment domain, GSDMD gasdermin D, APN adiponectin, SP substance P, SGLT-1 sodium–glucose cotransporter 1, AMPK adenosine monophosphate-activated kinase