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 CX 3 CR1, 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 CX 3 CR1 allele CX 3 CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX 3 CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

“…Bars represent mean6SD (n=10 number. 26,27 The number of renal DCs in Ccr2 2/2 mice was not impaired compared with the number in WT mice, confirming that the presence of renal DCs was not sufficient to protect from renal lesion (Supplemental Figure 2B). …”

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

“…In this paper, we report a previously undescribed antifibrotic effect of CX 3 CR1: it reduced the inflammation-induced proliferation of TGF-b-producing renal macrophages, which are critically important in experimental kidney fibrosis (15)(16)(17)(18). This finding was unexpected, given the proinflammatory and profibrotic properties of CX 3 CR1 not only in diseases of the kidney (3,49,54,(57)(58)(59)65), but also of the lung (75), liver (50), intestine (28), skin (55), arteriosclerotic vessels (76), and the CNS (33). CX 3 CR1 has been shown to contribute to the inflammatory recruitment of monocytes from the circulation into all these organs (44).…”

“…The chemokine receptor CX 3 CR1 has been shown to promote renal inflammation in several models (3,49,54,(57)(58)(59)65). Given that chronic kidney inflammation often leads to fibrosis, we hy- pothesized that CX 3 CR1 deficiency should attenuate renal fibrosis.…”

“…CX 3 CR1 deficiency reduced entry of their progenitors into the kidney and attenuated symptoms and fibrosis in ischemia/reperfusion injury (44,49), hypertensive kidney damage (54), and crescentic glomerulonephritis (3,57). In contrast, the loss of renal phagocytes aggravated renal candidiasis (58) but not pyelonephritis (3). Also, studies on human biopsy material from fibrotic kidneys described upregulation of CX 3 CR1, supporting a pathogenic role (59).…”

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…30 Its role in aortic accumulation of other leukocytes has not been reported. Second, CX3CR1 inhibits apoptosis of smooth muscle cells 31 2/2 macrophages undergo excess cell death in hepatic fibrosis 36 and renal candidiasis 37 and fibrosis. 38 CX3CR1 is upregulated on T cells in inflammation, CX3CR1 protects T H2 and T H1 cells from apoptosis, and cytokine production is higher in CX3CR1 + than CX3CR1 -T H1 cells.…”