Calling DCs to the kidney
Crescentic glomerulonephritis (GN) is an aggressive form of kidney disease that if left untreated can rapidly lead to acute renal failure and death within months. In healthy kidneys, dendritic cells (DC) form a network that functions in tissue homeostasis and acts as surveillance for signs of injury or infection. In a murine model of GN, DC-dependent inflammation has been shown to promote GN progression. Katharina Hocheiser and colleagues at Rheinische Friedrich-Wilhelms University demonstrate that signaling through the chemokine receptor CX3CR1 affects the abundance of DCs in the kidney. Deletion of the gene encoding CX3CR1 in the mouse model of GN attenuated disease severity. The results from this study indicate that targeting CX3CR1 has potential therapeutic benefits for patients with crescentic glomerulonephritis. The above confocal image depicts the infiltration of dendritic cells into the inflamed kidney in a mouse model of GN. Inflammatory dendritic cells are green, MHC II is red, blood vessels are blue, and connective tissue is white.
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Abstract
DCs and macrophages both express the chemokine receptor CX3CR1. Here we demonstrate that its ligand, CX3CL1, is highly expressed in the murine kidney and intestine. CX3CR1 deficiency markedly reduced DC numbers in the healthy and inflamed kidney cortex, and to a lesser degree in the kidney medulla and intestine, but not in other organs. CX3CR1 also promoted influx of DC precursors in crescentic glomerulonephritis, a DC-dependent aggressive type of nephritis. Disease severity was strongly attenuated in CX3CR1-deficient mice. Primarily CX3CR1-dependent DCs in the kidney cortex processed antigen for the intrarenal stimulation of T helper cells, a function important for glomerulonephritis progression. In contrast, medullary DCs played a specialized role in inducing innate immunity against bacterial pyelonephritis by recruiting neutrophils through rapid chemokine production. CX3CR1 deficiency had little effect on the immune defense against pyelonephritis, as medullary DCs were less CX3CR1 dependent than cortical DCs and because recruited neutrophils produced chemokines to compensate for the DC paucity. These findings demonstrate that cortical and medullary DCs play specialized roles in their respective kidney compartments. We identify CX3CR1 as a potential therapeutic target in glomerulonephritis that may involve fewer adverse side effects, such as impaired anti-infectious defense or compromised DC functions in other organs.
Authors
Katharina Hochheiser, Christoph Heuser, Torsten A. Krause, Simon Teteris, Anissa Ilias, Christina Weisheit, Florian Hoss, André P. Tittel, Percy A. Knolle, Ulf Panzer, Daniel R. Engel, Pierre-Louis Tharaux, Christian Kurts
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ISSN: 0021-9738 (print), 1558-8238 (online)