Bone Marrow Ly6Chigh Monocytes Are Selectively Recruited to Injured Kidney and Differentiate into Functionally Distinct Populations

Abstract

Roles for monocyte/macrophages (Mφ) in directing the development of tissue fibrosis are increasingly recognized. Macrophages form a heterogeneous group of inflammatory leukocytes, and the mechanisms by which they acquire heterogeneity and its functional significance are unclear. We used the unilateral ureteral obstruction model of progressive kidney fibrosis to explore macrophage heterogeneity and function further. Unilateral ureteral obstruction kidney Mφs form three distinct subpopulations defined by the marker Ly6C, all of which are derived from a single Ly6Chigh bone marrow monocyte population selectively recruited to the kidney. Conditional ablation of these Mφs in vivo in CD11b-DTR mice is potently antifibrotic. The mRNA transcription profile of these populations is consistent with differential functional roles for each subpopulation, with Ly6Clow macrophages transcribing genes consistent with selective profibrotic or M2-type function. Furthermore, bone marrow chimerism studies indicate that although resident kidney macrophages proliferate markedly to comprise up to 40% of the inflammatory macrophage population, they do not contribute to fibrosis. Our data identify Ly6C as a marker of functionally discrete tissue macrophage subsets and support a model of selective recruitment of Ly6Chigh bone marrow monocytes to the kidney that differentiate into three populations of kidney macrophages, including a profibrotic Ly6Clow population.

Microglia and Monocyte-Derived Macrophages in Stroke

“…In renal tubulointerstitial damage, bone marrow-derived Ly-6C hi monocytes polarized to M1 macrophages in the early phase of inflammation but polarized to M2 macrophages in the later phase when the inflammation was receding. In contrast, the Ly-6C lo monocyte subset recruited during inflammation only differentiated into M2 macrophages [109,110]. The differentiated macrophages can convert to other phenotypes in the specific local microenvironment, and conversion of early differentiated M1 macrophages into inflammation-resolving M2 macrophages occurs in the periphery [111].…”

Lung Pericytes and Resident Fibroblasts

“…Resident tissue macrophages have unexpectedly but commonly been found to react with low sensitivity to signals from microbes or damage, and to respond without producing high levels of proinflammatory and profibrotic cytokines. 53,57,58,68,69 One potential explanation is that because alveolar macrophages and similar resident cells are highly exposed to and must cope with foreign stimuli they are tuned to low reactivity, and therefore cannot be deployed as sentries. By contrast, positioning cells with immune sensory and response capabilities beneath endothelial and epithelial layers might better enable a sensitive reaction to distress, invasion, or breach of these barriers.…”

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

“…In the unilateral IRI model of kidney disease, ephrinB2 DV kidneys had more collagen deposition than WT kidneys (Supplemental Figure 5, C and D), consistent with a generalized role for PDZ-dependent signaling pathway in fibrogenesis. Because inflammatory macrophages responding to injury can promote fibrosis in the kidney, 20 we evaluated macrophage numbers and genes associated with macrophage activation and differentiation, but did not detect any differences in overall numbers or M1/M2 macrophage marker expression in any of mutant kidneys compared with WT kidneys (Supplemental Figure 6). …”

“…Interstitial fibrosis was assessed using picrosirius red-stained paraffin sections as described. 4,20 Picrosirius red + area was morphometrically defined and quantified. …”