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Exclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression
Katharina Hochheiser, … , Pierre-Louis Tharaux, Christian Kurts
Katharina Hochheiser, … , Pierre-Louis Tharaux, Christian Kurts
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(10):4242-4254. https://doi.org/10.1172/JCI70143.
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Research Article Nephrology

Exclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression

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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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Figure 3

CX3CR1 deficiency reduces intrarenal Th1 response and improves kidney function.

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CX3CR1 deficiency reduces intrarenal Th1 response and improves kidney fu...
(A) Absolute numbers of IFN-γ–producing CD4+ T cells and (B) of TNF-producing DCs and MPs per kidney of CX3CR1GFP/+ reporter mice and CX3CR1GFP/GFP-deficient mice 10 days after NTN induction, as determined by intracellular flow cytometry. In A, cell numbers in 4 individual experiments were given as percentage of the mean cell number in the CX3CR1-competent groups. (C) Creatinine clearance in CX3CR1GFP/+ and CX3CR1GFP/GFP mice 10 days after NTN induction. (D) Blood urea nitrogen in CX3CR1+/+ and CX3CR1GFP/GFP mice 10 days after NTN induction. (E) Albumin excretion normalized to creatinine by CX3CR1GFP/+ and CX3CR1GFP/GFP mice 10 days after NTN induction. Urine was collected for 12 hours. Data points represent individual mice, and results (A–C) are combined from 2 to 4 individual experiments, with 2 to 5 mice per group, or (D and E) are representative of 2 individual experiments, with 10 mice per group. Statistical significance was tested with the 2-tailed Mann-Whitney test.
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