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Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation
- Source :
- J Am Soc Nephrol
- Publication Year :
- 2020
-
Abstract
- BACKGROUND: AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. METHODS: We used mice with myeloid or macrophage cell–specific deletion of Irf4 (MΦ Irf4 (−/−)) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI. RESULTS: Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ Irf4 (−/−) mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4 (−/−) BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4 (−/−) mice or in wild-type mice with inhibition of AKT activity. CONCLUSIONS: Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.
- Subjects :
- 0301 basic medicine
Male
Macrophage polarization
urologic and male genital diseases
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
medicine
Renal fibrosis
Macrophage
Animals
Myeloid Cells
Letters to the Editor
Protein kinase B
Kidney
business.industry
Monocyte
General Medicine
Acute Kidney Injury
Macrophage Activation
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Basic Research
Nephrology
Reperfusion Injury
Interferon Regulatory Factors
Cancer research
Tubulointerstitial fibrosis
business
030215 immunology
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 32
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....77b1370af807832d2016f3f6c97c8edd