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Kidney macrophages are comprised of both monocyte-derived and tissue resident populations; however, the heterogeneity of kidney macrophages and factors that regulate their heterogeneity are poorly understood. Herein, we performed single cell RNA sequencing (scRNAseq), fate mapping, and parabiosis to define the cellular heterogeneity of kidney macrophages in healthy mice. Our data indicate that healthy mouse kidneys contain four major subsets of monocytes and two major subsets of kidney resident macrophages (KRM) including a population with enriched Ccr2 expression, suggesting monocyte origin. Surprisingly, fate mapping data using the newly developed Ms4a3Cre Rosa Stopf/f TdT model indicate that less than 50% of Ccr2+ KRM are derived from Ly6chi monocytes. Instead, we find that Ccr2 expression in KRM reflects their spatial distribution as this cell population is almost exclusively found in the kidney cortex. We also identified Cx3cr1 as a gene that governs cortex specific accumulation of Ccr2+ KRM and show that loss of Ccr2+ KRM reduces the severity of cystic kidney disease in a mouse model where cysts are mainly localized to the kidney cortex. Collectively, our data indicate that Cx3cr1 regulates KRM heterogeneity and niche-specific disease progression.

Additional file 1: Evaluation of C-1305 cytotoxicity in HeLa cells exposed for 6 hours to different concentrations of C-1305 and ER stressors, and supplementary materials for Figure 4 (three examples of the uncropped Western blots and SDS Page gels used to follow XBP1s changes).

Strain profiling was additionally conducted for Bacteroides vulgatus using StrainPhlAn across all samples, and 6 samples were able to show the relatedness of B. vulgatus strain. After DNA sequences from species-specific marker genes were aligned, a neighbor-joining (NJ) tree was constructed based on percentage identity (PID) distance between the marker genes using Jalview. The tree is drawn to scale bar unit (0.05) displayed below the tree. The presence of the related/unrelated B. vulgatus strain between mother and their infants was confirmed based on both WSS and StrainPhlAn (shaded color boxes on the NJ tree). The color boxes that were shown next to the NJ tree match the box colored labels shown in Figure 1(A).