Frontiers in Immunology (May 2023)
Cx3cr1 controls kidney resident macrophage heterogeneity
- Alex Yashchenko,
- Sarah J. Bland,
- Cheng J. Song,
- Ummey Khalecha Bintha Ahmed,
- Rachel Sharp,
- Isabella G. Darby,
- Audrey M. Cordova,
- Morgan E. Smith,
- Jeremie M. Lever,
- Jeremie M. Lever,
- Zhang Li,
- Ernald J. Aloria,
- Shuja Khan,
- Bibi Maryam,
- Shanrun Liu,
- Michael R. Crowley,
- Kenneth L. Jones,
- Lauren A. Zenewicz,
- James F. George,
- Michal Mrug,
- Michal Mrug,
- David K. Crossman,
- Katharina Hopp,
- Stavros Stavrakis,
- Mary B. Humphrey,
- Mary B. Humphrey,
- Florent Ginhoux,
- Kurt A. Zimmerman
Affiliations
- Alex Yashchenko
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Sarah J. Bland
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Cheng J. Song
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
- Ummey Khalecha Bintha Ahmed
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Rachel Sharp
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Isabella G. Darby
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Audrey M. Cordova
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Morgan E. Smith
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Jeremie M. Lever
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, United States
- Jeremie M. Lever
- Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
- Zhang Li
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
- Ernald J. Aloria
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
- Shuja Khan
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Bibi Maryam
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Shanrun Liu
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- Michael R. Crowley
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- Kenneth L. Jones
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Lauren A. Zenewicz
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- James F. George
- Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
- Michal Mrug
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, United States
- Michal Mrug
- Department of Veterans Affairs Medical Center, Birmingham, AL, United States
- David K. Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- Katharina Hopp
- 0Department of Medicine, Division of Renal Diseases and Hypertension, Polycystic Kidney Disease Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Stavros Stavrakis
- 1Department of Internal Medicine, Division of Cardiovascular Diseases, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Mary B. Humphrey
- 2Department of Internal Medicine, Division of Rheumatology, Immunology, and Allergy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Mary B. Humphrey
- 3Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States
- Florent Ginhoux
- 4Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, Singapore
- Kurt A. Zimmerman
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- DOI
- https://doi.org/10.3389/fimmu.2023.1082078
- Journal volume & issue
-
Vol. 14
Abstract
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.
Keywords
- macrophage heterogeneity
- kidney macrophages
- CX3CR1
- CCR2
- fate mapping
- single cell RNA sequencing (scRNAseq)
