Chronic Kidney Disease Is Characterized by Expansion of a Distinct Proinflammatory Intermediate Monocyte Subtype and by Increased Monocyte Adhesion to Endothelial Cells

Abstract

Significance Statement CKD is accompanied by abnormal inflammation, which contributes to progressive loss of functional renal tissue and accelerated cardiovascular disease. Although studies have documented that dysregulation of monocyte maturation and function is associated with CKD and its complications, it is not well characterized. This study reveals that a distinctive human monocyte subtype with high propensity for releasing proinflammatory mediators and activating endothelial cells is increased in adults with CKD compared with adults with high cardiovascular risk and normal kidney function. It also demonstrates that human monocyte adhesion to endothelial layers and responses to specific inflammatory migration signals are enhanced in CKD. These findings offer insights into the mechanisms of CKD-associated intravascular and localized inflammation and may suggest potential targets for therapeutic interventions. Background Cardiovascular disease (CVD) in patients with CKD is associated with increased circulating intermediate monocytes (IMs). Dysregulation of monocyte maturation and function is associated with CKD and its complications, but it is incompletely characterized. Methods To explore monocyte repertoire abnormalities in CKD, we studied properties of monocyte subpopulations, including IM subpopulations distinguished by HLA-DR expression level, in individuals with or without CKD. Using flow cytometry, we profiled monocyte populations in blood samples from adults with CKD, healthy volunteers (HVs), and patient controls (PCs) with high CVD risk. Monocyte subpopulations were also derived from single-cell RNA-sequencing profiles of paired blood and biopsy samples from kidney transplant recipients. We quantified intracellular cytokine production, migration, and endothelial adhesion in ex vivo assays of PBMCs. Results Of four predefined blood monocyte subpopulations, only HLA-DRhi IMs were increased in individuals with CKD compared with HVs and PCs. In HVs and patients with CKD, LPS-stimulated HLA-DRhi IMs isolated from blood produced higher amounts of TNF and IL-1β than other monocyte populations. Single-cell analysis revealed four monocyte clusters common to blood and kidneys, including an HLA-DRhi IM–like cluster that was enriched in kidneys versus blood. Migration toward CCL5 and CX3CL1 and adhesion to primary endothelial cell layers were increased in monocyte subpopulations in individuals with CKD compared with HVs. Monocyte adhesion to endothelial cells was partly dependent on CX3CR1/CX3CL1 interaction. Conclusions CKD is associated with an increased number of a distinctive proinflammatory IM subpopulation and abnormalities of monocyte migration and endothelial adhesion. Dysregulated monocyte maturation and function may represent targetable factors contributing to accelerated CVD in CKD.

The causal relationship between circulating leukocytes and kidney function: A Mendelian randomization study

“…As evidenced by Huang et al, a signi cant relationship between neutrophil and monocyte counts with proteinuria was found among 12,225 normal, healthy individuals who underwent hospital examinations [49]. In addition, Cormican et al discovered that only intermediate monocytes (IMs) with high human leukocyte antigen (HLA)-DR expression levels increased in individuals with CKD compared with healthy controls, indicating different monocyte subpopulations may play different roles in the process of in uencing eGFR [50].…”

The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging

“…Interestingly, chronic kidney disease is associated with increased numbers of HLA-DR high circulating proinflammatory intermediate monocytes, increased migration toward CCL5, and adhesion to primary endothelial cell layers 33 . In the aged mouse brain, it has been reported that parenchymal border macrophages comprise of less Lyve-1 + cells and more MHC-II + cells 11,34 .…”

“…While the MHC-II high subset receives modest monocyte contribution and is not continually replaced, the CCR2 + subset is almost entirely replaced by monocytes and is therefore more dynamic. Interestingly, chronic kidney disease is associated with increased numbers of HLA-DR high circulating pro-inflammatory intermediate monocytes, increased migration toward CCL5, and adhesion to primary endothelial cell layers 33 . In the aged mouse brain, it has been reported that parenchymal border macrophages comprise of less Lyve-1 + cells and more MHC-II + cells 11, 34 .…”

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

“…In ammatory PT cells may also receive signaling from stromal cells as they expressed receptors for FAS and TWEAK (Fig. 4F), while the ligands were expressed by NK cells (FAS) and monocytes (TWEAK), with both these cell types being implicated in kidney disease (19,30). While these are classically considered pro-apoptotic factors, they can also promote in ammation via NF-κβ signaling (31,32) and hence enable bi-directional cross talk between leucocytes and in ammatory PT cells to mediate renal in ammation.…”