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Clec7a expression in inflammatory macrophages orchestrates progression of acute kidney injury
Yaqiong Wang1,2,3,4,5, Xianzhe Li1,2,3,4,5, Xialian Xu1,2,3,4,5
1Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Acute kidney injury (AKI) is associated with high risk of mortality, post-disease renal fibrosis, kidney dysfunction and renal failure. Renal macrophages play a key role in the pathogenesis (M1 subpopulation), healing and remodeling (M2 subpopulation) in AKI and, thus, have been a promising target for clinical treatment of AKI. Here, in a mouse renal ischemia/reperfusion injury (IRI) model for AKI, we showed that renal macrophages could be further classified into Clec7a+ M1 macrophages, Clec7a- M1 macrophages, Clec7a+ M2 macrophages and Clec7a- M2 macrophages, representing distinct macrophage populations with different functionality. Interestingly, Clec7a+ M1 macrophages exhibited potent pro-inflammatory and phagocytic effects compared to Clec7a- M1 macrophages, while Clec7a- M2 macrophages exhibited better proliferating and migrating potential, which is critical for their role in tissue repairing after injury. These data from mice were further strengthened by bioinformatics analyses using published database. In vivo, combined expression of Clec7a in M1 macrophages and depletion of Clec7a in M2 macrophages significantly improved the renal function after IRI-AKI. Together, our data suggest that Clec7a is crucial for the fine regulation of macrophage phenotype during AKI and could be a novel target for boosting clinical therapy.
Insights
Clec7a+ M1 macrophages are pro-inflammatory, while Clec7a- M2 macrophages promote tissue repair in acute kidney injury (AKI). Targeting Clec7a improves kidney function after injury.
Area of Science:
- Immunology
- Nephrology
- Cell Biology
Background:
- Acute kidney injury (AKI) leads to high mortality and kidney failure.
- Renal macrophages, including M1 and M2 subpopulations, are critical in AKI pathogenesis and repair.
- Current AKI therapies require novel targets for improved clinical outcomes.
Purpose of the Study:
- To investigate the distinct functional roles of Clec7a-expressing macrophage subsets in AKI.
- To determine if Clec7a plays a role in regulating macrophage phenotype during kidney injury.
- To evaluate Clec7a as a potential therapeutic target for AKI.
Main Methods:
- Utilized a mouse model of renal ischemia/reperfusion injury (IRI) to induce AKI.
- Classified renal macrophages into four subsets based on Clec7a expression and M1/M2 markers.
- Employed bioinformatics analysis of public databases to corroborate findings.
- Assessed renal function following targeted manipulation of Clec7a expression in macrophage subsets *in vivo*.
Main Results:
- Identified four distinct renal macrophage populations: Clec7a+ M1, Clec7a- M1, Clec7a+ M2, and Clec7a- M2.
- Clec7a+ M1 macrophages displayed enhanced pro-inflammatory and phagocytic activity.
- Clec7a- M2 macrophages showed superior proliferation and migration, crucial for tissue repair.
- Combined *in vivo* strategies of Clec7a expression in M1 and depletion in M2 macrophages significantly improved renal function post-IRI-AKI.
Conclusions:
- Clec7a is essential for fine-tuning macrophage phenotypes during AKI.
- Specific manipulation of Clec7a in distinct macrophage subsets offers a promising therapeutic strategy for AKI.
- Clec7a represents a novel target for enhancing clinical treatments of acute kidney injury.
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