Macrophage Heterogeneity in Kidney Injury and Fibrosis

Abstract

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C+ monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases.

Macrophages of the “Heart-Kidney” Axis: Their Dynamics and Correlations with Clinical Data and Outcomes in Patients with Myocardial Infarction

“…However, plasma renin in these mice remained elevated for 28 days after aortic transverse constriction, which indicates activation of the reninangiotensin-aldosterone system (RAAS), an inducer of cardiac hypertrophy and fibrosis. In this case, the absence of hypertrophy and fibrosis in mice probably indicates that a certain threshold of the plasma level of GM-CSF is required to activate RAAS-induced cardiac remodeling [12]. Interestingly, Ly6Clo transplantation into Klf5KO mice lead to a significant improvement in survival after transverse aortic narrowing, while transplantation of Ly6Chi, an analogue of M1 macrophages in humans, did not show this effect [7].…”

“…Previous results on the role of the innate immunity system in post-infarction myocardial regeneration in humans and animals [8,10,11] and its place in cardiorenal interactions in animals provided the rationale for studying this issue [6,7,12,13]. Involvement of monocytes/macrophages in both the inflammatory and regenerative phases of post-infarction myocardial remodeling has already been confirmed by the presence of their prolonged CD68+, CD163+, CD206+ and stabilin-1+ macrophage infiltration in both IA and non-IA of the myocardium in patients who experienced a fatal MI [10].…”

“…In addition, monocytes were also studied in the peripheral blood of patients with CKD and undertaking dialysis [14,15]. It was shown that the number of circulating classical monocytes CD14+ and CD16−, can predict the development of cardiovascular events and death in patients with CKD [12]. Experimental studies conducted with rodents showed that kidney macrophage polarization under ischemic conditions can affect cardiac macrophage polarization by activating the paracrine signaling pathway, which ultimately promotes the development of adaptive hypertrophy and fibrosis of the myocardium, which underlie its remodeling [7,18].…”

The Roles of Macrophages in Heart Regeneration and Repair After Injury

“…In mice, macrophages produced about 6.8% of total collagen ( 94 ). Since macrophages could exhibit a fibrosis-associated phenotype, some researchers proposed that macrophages could go through a fibroblast-like transition after ischemic injury ( 93 , 95 , 96 ).…”

Three-Dimensional Visualization With Tissue Clearing Uncovers Dynamic Alterations of Renal Resident Mononuclear Phagocytes After Acute Kidney Injury

“…These phenotypic changes could also indicate the M1/M2 polarization. Renal MNPs are characterized into two functionally distinct cell types: proinflammatory M1 and immune-regulatory and fibrotic M2 MNPs ( 43 ). CD86 and MHCII are representative M1-like phenotype markers.…”