Cx3cr1 controls kidney resident macrophage heterogeneity

Frontiers in Immunology

Immunology

Shanrun Liu¹  Kenneth L. Jones²  Rachel Sharp²  Zhang Li³  Cheng J. Song³  Ernald J. Aloria³  David K. Crossman⁴  Michael R. Crowley⁴  Stavros Stavrakis⁵  Bibi Maryam⁶  Sarah J. Bland⁶  Shuja Khan⁶  Morgan E. Smith⁶  Isabella G. Darby⁶  Audrey M. Cordova⁶  Alex Yashchenko⁶  Ummey Khalecha Bintha Ahmed⁶  Kurt A. Zimmerman⁶  Mary B. Humphrey⁷  Jeremie M. Lever⁸  Michal Mrug⁹  Katharina Hopp^1,10  Lauren A. Zenewicz^1,11  James F. George^1,12  Florent Ginhoux^1,13 

[1]Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, United States

[2]Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

[3]Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States

[4]Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States

[5]Department of Internal Medicine, Division of Cardiovascular Diseases, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

[6]Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

[7]Department of Internal Medicine, Division of Rheumatology, Immunology, and Allergy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

[8]Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States

[9]Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, United States

[10]Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States

[11]Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, United States

[12]Department of Veterans Affairs Medical Center, Birmingham, AL, United States

[13]Department of Medicine, Division of Renal Diseases and Hypertension, Polycystic Kidney Disease Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

[14]Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

[15]Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States

[16]Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, Singapore

关键词: macrophage heterogeneity;    kidney macrophages;    CX3CR1;    CCR2;    fate mapping;    single cell RNA sequencing (scRNAseq);    cystic kidney disease;    parabiosis;   

DOI  :  10.3389/fimmu.2023.1082078

 received in 2022-10-27, accepted in 2023-04-25,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Yashchenko, Bland, Song, Ahmed, Sharp, Darby, Cordova, Smith, Lever, Li, Aloria, Khan, Maryam, Liu, Crowley, Jones, Zenewicz, George, Mrug, Crossman, Hopp, Stavrakis, Humphrey, Ginhoux and Zimmerman