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Abstract
The presence of monocytes and macrophages in kidney biopsies has been associated with kidney injury and poor prognosis in lupus nephritis. Infiltrating and residential subtypes may acquire specialized functions in response to kidney damage that drive homeostatic or aberrant tissue remodeling. The functions and cellular differentiation of monocytes and macrophages in kidneys have been difficult to study due to the inability to collect immune cells from small human kidney biopsies as well as technical limitations to deeply phenotype cells. We previously reported on the characterization of 466 kidney monocytes and macrophages collected from the kidney biopsies of 24 patients with lupus nephritis using plate-based single cell RNA seq. Here, we have characterized ~22,000 kidney monocytes and macrophages collected from 155 lupus nephritis patient biopsies with droplet-based single cell RNA seq. Our analysis of this comprehensive data set has revealed deep new insights into the cellular identities and the potential roles of monocyte and macrophage subsets in lupus nephritis (figure 1). Critically, we identified phagocytic macrophages that were positively associated with the histopathologic activity index suggesting an important role for these cells and their functional gene programs that regulate cellular debris clearance and lipid metabolism (figure 2). We also identified infiltrating populations of CD16+ and CD14+ monocytes, and residential LYVE1+ and LYVE1- macrophages (figure 1).
Interestingly each infiltrating and residential cellular subset appeared to differentiate into these phagocytic macrophages in our trajectory analysis, suggesting that distinct cellular subsets converged on this common phagocytic state (figure 1). These phagocytic macrophages were infrequent in kidney biopsies collected from patients with non-autoimmune kidney disease from hypertension and diabetes (figure 3). Together, our findings suggest that phagocytic macrophages may play an important role in kidney remodeling and that these cells originated from distinct infiltrating and residential populations in response to kidney lesions found in lupus nephritis.
Singlle-cell RNA sequencing identifies myelloid subsets in kidney biopsies from patiients with act1ive lupus nephritis. ~22,000 intrarenal monocytes and macrophages from 155 lupus nephritis patient biopsies were collected for single cell RNA-seq that enabled celllular identification (colored clusters). Trajectory analysis (black arrows) reveals that phagocytic macrophagies were derived from 4 distinct populatiions of infilltrating and residentia’I macrophagies (from bottom clockwiise: infiltrating CD14+ & CD16+ monocytes, residential LYVE1+ and LYVE1 macrophages).
Phagocytiic macrophages (and smaller subsets of LYVE1+ and LYVE1 cells) were associated with the activity index in covarying neighborhood analysis, an unbiased method to identify associations between cell popullations in singl e ce’II RNA-seq and clinical data.
Phagocytic macmphages in lupus nephritis are infrequent in diabetic and hypertensive kidney disease.Fig. 3 Phagocytic macrophages (red outlines) and a small subset of LYVE1+ macrophages in lupus nephritis are infrequent iin kidney biopsies from patients with diabetes and hypertension. lntrarenal myeloiidlcells from 155 lupus neplhriitis and 45 chronic kidney disease patients were integrated.
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