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

Abstract

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C high monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.

A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury

“…the prior study did not exclude transient AKI of short duration. Our GWAS also failed to confirm findings from a previously published candidate gene study using mouse models (37). This is not unexpected as there is a growing body of literature suggesting that the overlap between murine and human transcriptomes is minimal (38)(39)(40).…”

CX3CR1-dependent endothelial margination modulates Ly6Chigh monocyte systemic deployment upon inflammation in mice

“…In the course of cecal ligature and punctureinduced sepsis, we reported that CX3CR1-dependent Ly6C high -Mo adherence to the renal endothelium exerts a protective effect against kidney injuries. 19 Herein, we extended the role of CX3CR1 in the systemic distribution of Ly6C high -Mo during the early phase of acute inflammation. It is likely that monocyte adherence to the endothelium is an important feature of the compensatory anti-inflammatory response syndrome, 31,32 through interleukin-1 receptor alpha release for instance, 19 and through the cleaning of amyloid b, 33 dead cells, and potential pathogens in the vasculature.…”

“…19 Herein, we extended the role of CX3CR1 in the systemic distribution of Ly6C high -Mo during the early phase of acute inflammation. It is likely that monocyte adherence to the endothelium is an important feature of the compensatory anti-inflammatory response syndrome, 31,32 through interleukin-1 receptor alpha release for instance, 19 and through the cleaning of amyloid b, 33 dead cells, and potential pathogens in the vasculature. 25 Margination was still increased at day 7 in CLP-operated mice, suggesting that the regulation between marginated and circulating cells is not only a feature of acute inflammation (data not shown).…”

“…For cecal ligation and puncture (CLP) -induced peritonitis, mice were operated as previously performed. 19 In some experiments, 50 mg of CX3CR1 antagonist (F1) antagonist 20 was injected IV into sterile PBS concomitantly with LPS injection or immediately and 3.5 hours after CLP.…”

The Changing Landscape of Renal Inflammation

“…The human relevance of potentially protective CX 3 CR1-bearing cells is suggested by the reduced risk of acute kidney injury (AKI) during sepsis of patients expressing the I249 CX 3 CR1 polymorphism, which functionally increases CX 3 CR1-mediated monocyte binding to CX 3 CL1, its cognate ligand. [94] Thus, patrolling monocytes appear to play an important function in maintaining endothelium integrity and thus potentially, immune homeostasis. Of note, CX 3 CR1 is also expressed on CD11c + DCs recruited to the kidney cortex during NTN, an immune-complex mediated disease.…”