CX3CR1-dependent renal macrophage survival promotes Candida control and host survival
Michail S. Lionakis, … , Mihai G. Netea, Philip M. Murphy
Michail S. Lionakis, … , Mihai G. Netea, Philip M. Murphy
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5035-5051. https://doi.org/10.1172/JCI71307.
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Research Article Infectious disease

CX3CR1-dependent renal macrophage survival promotes Candida control and host survival

Abstract

Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1–/– mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1–/– mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.

Authors

Michail S. Lionakis, Muthulekha Swamydas, Brett G. Fischer, Theo S. Plantinga, Melissa D. Johnson, Martin Jaeger, Nathaniel M. Green, Andrius Masedunskas, Roberto Weigert, Constantinos Mikelis, Wuzhou Wan, Chyi-Chia Richard Lee, Jean K. Lim, Aymeric Rivollier, John C. Yang, Greg M. Laird, Robert T. Wheeler, Barbara D. Alexander, John R. Perfect, Ji-Liang Gao, Bart-Jan Kullberg, Mihai G. Netea, Philip M. Murphy

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Figure 6

Cx3cr1 deficiency increases apoptosis of kidney macrophages, but does not affect kidney macrophage differentiation or proliferation or monocyte trafficking from blood to kidney.

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Cx3cr1 deficiency increases apoptosis of kidney macrophages, but does no...
(A) Kidney macrophage proliferation. Leukocytes were purified from kidneys of the indicated mouse lines, and endogenous MHCIIhiF4/80hiCD11b+ cells were analyzed for Ki67 expression (n = 6–10; 2 independent experiments). (B) Monocyte trafficking from blood to kidney after Candida infection. Adoptive transfer of BM-derived monocytes from the indicated uninfected mouse lines into WT mice 3 days after Candida infection. WT recipient mice were sacrificed 12 hours after cell transfer, and the number of GFP+ monocytes purified from kidneys was measured (n = 6–8; 2 independent experiments). (C) Endogenous monocyte accumulation in kidney after Candida infection (n = 9–15; 3 to 4 independent experiments). (D) Macrophage differentiation. WT recipient mice were sacrificed 3 days after cell transfer, and the percentage of GFP+ cells from the indicated uninfected mouse lines that differentiated into MHCIIhiF4/80hiCD11b+ macrophages in kidneys was determined. (n = 6; 2 independent experiments). (E) Persistence of macrophages in the infected kidney 3 days after monocyte transfer is Cx3cr1 dependent. Left, quantitation. *P = 0.001 (n = 6; 2 independent experiments). Right, representative FACS plots. (F) Endogenous kidney macrophage survival before and after Candida infection. *P < 0.05; **P < 0.01; ***P < 0.001 (n = 6–8; 2 independent experiments). (G) Representative FACS plots for survival marker expression by kidney macrophages of uninfected mice quantified in F. (H) Cx3cr1 modulates caspase-3 cleavage and Akt phosphorylation. Endogenous kidney macrophages were sorted from Candida-infected kidneys 6 days after infection. Left, representative Western blot; middle and right, quantitation of Western blot data. β-actin is shown as loading control. *P = 0.03; **P < 0.01 (n = 4; 2 independent experiments). All quantitative data represent mean ± SEM.