Opposing Roles of Dendritic Cell Subsets in Experimental GN : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Brähler, Sebastian; Zinselmeyer, Bernd H.; Raju, Saravanan; Nitschke, Maximilian; Suleiman, Hani; Saunders, Brian T.; Johnson, Michael W.; Böhner, Alexander M.C.; Viehmann, Susanne F.; Theisen, Derek J.; Kretzer, Nicole M.; Briseño, Carlos G.; Zaitsev, Konstantin; Ornatsky, Olga; Chang, Qing; Carrero, Javier A.; Kopp, Jeffrey B.; Artyomov, Maxim N.; Kurts, Christian; Murphy, Kenneth M.; Miner, Jeffrey H.; Shaw, Andrey S.

1Department of Pathology and Immunology,

2Division of Nephrology, Department of Medicine, and

10Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri;

3Department II of Internal Medicine and

4Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany;

5Research Biology, Genentech, South San Francisco, California;

6Institute of Experimental Immunology, University Clinic of the Rheinische Friedrich Wilhelms Universität, Bonn, Germany;

7Computer Technologies Department, ITMO University, St. Petersburg, Russia;

8Fluidigm Inc., Markham, Ontario, Canada; and

9Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence: Dr. Bernd H. Zinselmeyer, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110, or Dr. Andrey S. Shaw, Genentech, One DNA Way, Mail Stop 93b, South San Francisco, CA 94080 Email: [email protected] or [email protected]

Abstract

Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD11c reporter mouse line and two mouse lines with DC-specific reporters, Zbtb46_-GFP and Snx22_-GFP. Multiphoton microscopy of kidney sections confirmed that most of the dendritically shaped CD11c+ cells forming a network throughout the renal interstitium expressed macrophage-specific markers. In contrast, DCs marked by Zbtb46_-GFP or Snx22_-GFP were less abundant, concentrated around blood vessels, and round in shape. We confirmed this pattern of localization using imaging mass cytometry. Motility measurements showed that resident macrophages were sessile, whereas DCs were motile before and after inflammation. Although uninflamed glomeruli rarely contained DCs, injury with nephrotoxic antibodies resulted in accumulation of ZBTB46+ cells in the periglomerular region. ZBTB46 identifies all classic DCs, which can be categorized into two functional subsets that express either CD103 or CD11b. Depletion of ZBTB46+ cells attenuated the antibody-induced kidney injury, whereas deficiency of the CD103+ subset accelerated injury through a mechanism that involved increased neutrophil infiltration. RNA sequencing 7 days after nephrotoxic antibody injection showed that CD11b+ DCs expressed the neutrophil-attracting cytokine CXCL2, whereas CD103+ DCs expressed high levels of several anti-inflammatory genes. These results provide new insights into the distinct functions of the two major DC subsets in glomerular inflammation.