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Updated: Jan 27, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
miR-378a Modulates Macrophage Phagocytosis and Differentiation through Targeting CD47-SIRPα Axis in Atherosclerosis
Wenna Chen1,2, Ximing Li1, Junyan Wang3
1Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China.
Background:
Signal regulatory protein alpha (SIRPa) is an essential signalling molecule that modulates inflammatory responses in macrophages. However, the regulation of SIRPs and its dynamic changes in macrophages under inflammatory stimulation in atherosclerosis remain uncertain.
Objective:
The study aimed to identify the miRNAs that regulate SIRPa transcription and their roles in modulating phagocytosis, differentiation and cholesterol efflux in macrophages.
Methods:
ApoE knockout mice were fed with a high-fat diet for 12 weeks. Intimal lesion areas and lipid accumulation were assessed by haematoxylin and eosin (HE) and oil red O staining. The expression of mRNAs/miRNAs was assessed by RNA-seq (RNA sequencing) and RT-qPCR (real-time quantitative polymerase chain reaction). The identification of miR-378a associated with SIRPa regulation in macrophages induced by ox-LDL was confirmed by RT-qPCR and Western blot. The phagocytosis and differentiation of macrophages were detected to figure out the role of miR-378a and SIRPa.
Results:
SIRPa was proved to be a target of miR-378a. Reduced miR-378a can promote the expression of SIRPa. RNA-seq data showed that the levels of mRNA associated with macrophage phenotypes and SIRPa-CD47 axis were increasing significantly with a decreasing phagocytic phenotype in ApoE-/- mice vs wild-type (WT) mice (P < 0.01). The level of miR-378a was reduced in the aorta of ApoE-/- mice vs WT mice. The experiment in vitro showed that overexpression of miR-378a in macrophages decreased the level of Sirpa mRNA obviously vs control (P < 0.01). The phagocytic activity of miR-378a-transfected macrophages was promoted vs control (P < 0.05). miR-378a significantly depleted Sirpa levels in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages (P < 0.05), and depletion of miR-378a reversed Sirpa reduction obviously (P < 0.05). miR-378a promoted the secretion of TNF-a and IL-6 indirectly.
Conclusion:
It has been demonstrated that miR-378a regulates SIRPa-mediated phagocytosis and polarization of macrophages by a direct or indirect way. This research may provide a new path to promote reverse cholesterol transport of macrophages and hinder the progress of atherosclerosis.
Insights
MicroRNA-378a (miR-378a) regulates signal regulatory protein alpha (SIRPa) in macrophages, impacting atherosclerosis. Reduced miR-378a increases SIRPa, impairing phagocytosis and promoting inflammation, offering potential therapeutic targets.
Area of Science:
- Molecular Biology
- Immunology
- Cardiovascular Research
Background:
- Signal regulatory protein alpha (SIRPa) is crucial for macrophage inflammatory responses.
- Regulation and dynamic changes of SIRPa in macrophages during atherosclerosis are not fully understood.
- Atherosclerosis involves complex macrophage behavior, including phagocytosis and lipid accumulation.
Purpose of the Study:
- To identify microRNAs (miRNAs) regulating SIRPa transcription in macrophages.
- To investigate the role of identified miRNAs in modulating macrophage phagocytosis, differentiation, and cholesterol efflux.
- To explore the therapeutic potential of miRNA-mediated SIRPa regulation in atherosclerosis.
Main Methods:
- Utilized ApoE knockout mice on a high-fat diet to model atherosclerosis.
- Employed RNA sequencing (RNA-seq) and RT-qPCR for mRNA and miRNA expression analysis.
- Confirmed miR-378a's regulatory role on SIRPa in macrophages using RT-qPCR and Western blot, assessing phagocytosis and cytokine secretion.
Main Results:
- miR-378a directly targets and downregulates SIRPa expression.
- Reduced miR-378a levels in atherosclerotic mice correlated with increased SIRPa and impaired macrophage phagocytosis.
- Overexpression of miR-378a in macrophages enhanced phagocytic activity and modulated inflammatory cytokine (TNF-a, IL-6) secretion.
Conclusions:
- miR-378a plays a significant role in regulating SIRPa-mediated macrophage phagocytosis and polarization.
- The miR-378a/SIRPa axis represents a potential therapeutic target for promoting reverse cholesterol transport.
- This research offers a novel strategy to impede atherosclerosis progression by modulating macrophage function.
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