Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis
Abstract
1. Introduction
2. Cellular Composition of the Heart
2.1. Fibroblasts in Cardiac Tissue
2.2. Macrophages in Cardiac Tissue
3. Interactions between Cardiac Macrophages and Fibroblasts
3.1. TGFβ
3.2. IL-4 and IL-6
3.3. IL-17A
3.4. MMP-2, MMP-9, and MMP-12
3.5. CX3CR 1
3.6. microRNA-21
3.7. microRNA-155
3.8. TLR2
4. Fibroblast–Macrophage Interactions for Novel Fibrosis Treatments
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Cardiovascular Disease | Model | Molecular Mechanisms | Main Outcome | References |
---|---|---|---|---|
TAC-induced cardiac pressure overload | C57BL/6j and CCR2−/− mice | Increased release of TGF-β1 and IL-10 from cardiac macrophages in TAC mice | Myofibroblast differentiation and collagen production | [45] |
Cardiac fibrosis with diastolic dysfunction | Patients with hypertension and HFpEF; 8–30 wk-old CCR2−/−, CX3CR1CreER and IL10fl/fl C57BL/6 mice | IL-10 contributes to a macrophage phenotype shift toward a profibrotic subset, which activates fibroblasts | Cardiac fibrosis with diastolic dysfunction | [60] |
Inflammatory dilated cardiomyopathy (DCMi) | 6–10 wk-old WT, IL17ra−/− BALB/cJ and CBy.PL(B6)-Thy1a/ScrJ (Thy1.1) founder mice | IL-17A induces the production of GM-CSF by CFs, leading to infiltration of Ly6Chigh MO/MΦs | IL-17A directs the conversion of Ly6Chigh MO/MΦ trans to a more pro-inflammatory phenotype via CF-derived GM-CSF | [64] |
MI | 6–8 wk-old C57BL/6 mice and Trib1–/– mice of a mixed background of C57BL/6 and SV129 | IL-4 treatment increased the number of cardiac M2-like macrophages, which increased the activation of CFs | IL-4 is a potential biological drug for treating MI | [65] |
MI | 7–10 wk-old female WKY rats | CDCs reduce the number of CD68+ macrophages within the ischemic heart | CDC limits acute injury and attenuates cardiac fibrosis | [66] |
MI | 6–8 wk-old female WKY rats | Reduced levels of IL-1β and TNF-α in the peri-infarct region | CSps enhance cardiomyocyte proliferation and angiogenesis and attenuate hypertrophy and fibrosis | [67] |
AMI | Yucatan mini-pigs | / | IC delivery of allo-CDCs is safe, feasible, and effective in cardioprotection, reducing IS, preventing MVO, and attenuating adverse acute remodeling | [68] |
MI | 8–10 wk-old WT male C57BL/6 and MMP12−/− mice | Significantly increased mRNA expression of CXCL1, CXCL2, and CXCL5 in MMP12−/− mice | MMP-12 production by Ly6Clow macrophages promotes wound healing | [69] |
Molecules | Cellular Origin | Molecular Mechanisms | References |
---|---|---|---|
TGF-β | Macrophages, cardiomyocytes, and fibroblasts themselves | Activation of downstream SMAD3 via TGF-β receptor 1/ALK5 in fibroblasts induced activated fibroblasts to express αSMA, collagen I, Comp, periosteal proliferator protein, and CTGF | [61] |
IL-4 | / | Inhibition of the increase in the number of M2-like macrophages and increase in the activation level of fibroblasts improve the prognosis of MI | [65,70] |
IL-6 | Macrophages and fibroblasts | IL-6 acts as a downstream signal for HIMF and activates the MAPK and CaMKII-STAT3 pathways | [71] |
IL-17A | / | IL-17A induces the production of chemokines by CFs, leading to an infiltration of neutrophils and Ly6Chigh MO/MΦs in the heart | [64] |
MMP-2, MMP-9, MMP-12 | Neutrophils and macrophages | MMP-2 and MMP-9 over-grade the ECM in the early stages of MI. MMP-12−/− mice show increased neutrophil numbers, upregulated MMP-9, and reduced fibrosis and myofibroblast numbers | [69,72] |
CX3CR 1 | Macrophages | Altered activity of CFs, resulting in decreased ECM content in the marginal zone and increased cardiac contractility | [73] |
microRNA-21 | Macrophages | MicroRNA-21 inhibits ERK signaling and enhances cardiac fibroblast survival by suppressing the expression of SPRY1 in CFs | [74] |
microRNA-155 | Macrophages and fibroblasts | MicroRNA-155 inhibits cardiac fibroblast proliferation by downregulating Sos1 expression and promotes inflammation by decreasing cytokine signaling inhibitor 1 expression | [75] |
TLR2 | Macrophages | TLR2 deficiency inhibits macrophage-dependent CF activation via modulation of the TGF-β/Smad2/3 pathway | [76] |
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Yang, B.; Qiao, Y.; Yan, D.; Meng, Q. Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis. Cells 2024, 13, 764. https://doi.org/10.3390/cells13090764
Yang B, Qiao Y, Yan D, Meng Q. Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis. Cells. 2024; 13(9):764. https://doi.org/10.3390/cells13090764
Chicago/Turabian StyleYang, Bo, Yan Qiao, Dong Yan, and Qinghang Meng. 2024. "Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis" Cells 13, no. 9: 764. https://doi.org/10.3390/cells13090764
APA StyleYang, B., Qiao, Y., Yan, D., & Meng, Q. (2024). Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis. Cells, 13(9), 764. https://doi.org/10.3390/cells13090764