Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease

Conway, Bryan; O’Sullivan, Eoin D.; Cairns, Carolynn; O’Sullivan, James; Simpson, Daniel J.; Salzano, Angela; Connor, Katie; Ding, Peng; Humphries, Duncan; Stewart, Kevin; Teenan, Oliver; Pius, Riinu; Henderson, Neil C.; Benezech, C; Ramachandran, Prakash; Ferenbach, David A.; Hughes, Jeremy; Chandra, Tamir; Denby, Laura

doi:10.1681/asn.2020060806

Cited by 139 publications

(139 citation statements)

References 73 publications

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“…Other studies [ 20 ] previously confirmed marked changes in the proportion and gene expression of at least 12 myeloid cell subsets involved in kidney injury and repair in a reversible UUO model. In addition, they described a novel Mmp121 macrophage subset that acts during repair.…”

Section: Discussionmentioning

confidence: 63%

Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model

Calle

Játiva²,

Torrico³

et al. 2021

Cells

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Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.

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Section: Discussionmentioning

confidence: 63%

Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model

Calle

Játiva²,

Torrico³

et al. 2021

Cells

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“…In the present study, we developed further in-depth analysis of these immune cell types with comprehensive classification and description of cell subtypes including their specific marker genes, functional characteristics, transcriptional regulation, and the proportional dynamics from the renal allograft rejection peak on D7 to the regression phase on D15. In naïve mouse kidneys, monocytes/macrophages, neutrophils, DCs, B and T lymphocytes, NK cells could all be observed (16,41,42). Among macrophage subtypes, infiltrating Ly6C hi Chil3 + macrophage and Ly6C lo patrolling macrophages are commonly found in normal kidneys (16,42), whereas IFNIC and Mrc1 + macrophages are more common to disease models like unilateral ureteric obstruction model (42).…”

Section: Discussionmentioning

confidence: 99%

“…In naïve mouse kidneys, monocytes/macrophages, neutrophils, DCs, B and T lymphocytes, NK cells could all be observed (16,41,42). Among macrophage subtypes, infiltrating Ly6C hi Chil3 + macrophage and Ly6C lo patrolling macrophages are commonly found in normal kidneys (16,42), whereas IFNIC and Mrc1 + macrophages are more common to disease models like unilateral ureteric obstruction model (42). Study of kidney allograft biopsies from human recipients undergoing AR and CR also identified immune populations like those in mice, including monocytes, B cells, T cells, plasma cells (43)(44)(45), therefore independently supporting a role of these cells in kidney rejection in humans.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals the Immunological Profiles of Renal Allograft Rejection in Mice

et al. 2021

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Allograft rejection is a common immunological feature in renal transplantation and is associated with reduced graft survival. A mouse renal allograft rejection model was induced and single-cell RNA sequencing (scRNA-seq) data of CD45+ leukocytes in kidney allografts on days 7 (D7) and 15 (D15) after operation was analyzed to reveal a full immunological profiling. We identified 20 immune cell types among 10,921 leukocytes. Macrophages and CD8+ T cells constituted the main populations on both timepoints. In the process from acute rejection (AR) towards chronic rejection (CR), the proportion of proliferating and naïve CD8+ T cells dropped significantly. Both B cells and neutrophils decreased by about 3 folds. On the contrary, the proportion of macrophages and dendritic cells (DCs) increased significantly, especially by about a 4.5-fold increase in Ly6cloMrc1+ macrophages and 2.6 folds increase in Ly6cloEar2+ macrophages. Moreover, myeloid cells harbored the richest ligand and receptor (LR) pairs with other cells, particularly for chemokine ligands such as Cxcl9, Cxcl10, Cxcl16 and Yars. However, macrophages with weak response to interferon gamma (IFNg) contributed to rejection chronicization. To conclude, reduction in CD8 T cells, B cells and neutrophils while increasing in Ly6cloMrc1+ macrophages and Ly6cloEar2+ macrophages, may contribute significantly to the progress from AR towards CR.

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“…Recent work has shed light on more refined strategies for separating mononuclear phagocyte cell (MPC) populations within the kidney and shows promise for enhancing our sophistication and accuracy when investigating these cells in the context of AKI. In addition to F4/80, flow cytometry studies have shown that CD11b, CD11c, CX3CR1, Ly6C, CD64, CD14, CD16, MHC II, and CD103 are also useful markers for delineating myeloid populations within the mouse kidney ( Table 1 ) ( 21 , 69 – 80 ). A study from Lee et al used several of these markers to identify a novel MPC population in the kidney that is also CD45-intermediate (CD45 int CD11b int F4/80 + MHCII + CX3CR1 + Ly6C − ).…”

Section: The Ambiguity Of F4/80mentioning

confidence: 99%

Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome

Nash

Okusa

2021

Front. Med.

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Immune dysregulation in acute kidney injury (AKI) is an area of intense interest which promises to enhance our understanding of the disease and how to manage it. Macrophages are a heterogeneous and dynamic population of immune cells that carry out multiple functions in tissue, ranging from maintenance to inflammation. As key sentinels of their environment and the major immune population in the uninjured kidney, macrophages are poised to play an important role in the establishment and pathogenesis of AKI. These cells have a profound capacity to orchestrate downstream immune responses and likely participate in skewing the kidney environment toward either pathogenic inflammation or injury resolution. A clear understanding of macrophage and myeloid cell dynamics in the development of AKI will provide valuable insight into disease pathogenesis and options for intervention. This review considers evidence in the literature that speaks to the role and regulation of macrophages and myeloid cells in AKI. We also highlight barriers or knowledge gaps that need to be addressed as the field advances.

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Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease

Cited by 139 publications

References 73 publications

Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model

Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model

Single-Cell RNA Sequencing Reveals the Immunological Profiles of Renal Allograft Rejection in Mice

Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome

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