Dendritic Cells and Macrophages: Sentinels in the Kidney

Abstract

The mononuclear phagocytes (dendritic cells and macrophages) are closely related immune cells with central roles in anti-infectious defense and maintenance of organ integrity. The canonical function of dendritic cells is the activation of T cells, whereas macrophages remove apoptotic cells and microbes by phagocytosis. In the kidney, these cell types form an intricate system of mononuclear phagocytes that surveys against injury and infection and contributes to organ homeostasis and tissue repair but may also promote progression of CKD. This review summarizes the general functions and classification of dendritic cells and macrophages in the immune system and recapitulates why overlapping definitions and historically separate research have created controversy about their tasks. Their roles in acute kidney disease, CKD, and renal transplantation are described, and therapeutic strategy to modify these cells for therapeutic purposes is discussed.

Keywords: immunology; immunology and pathology; immunosuppression; kidney disease; macrophages.

Figure 1.

Canonical functions of renal dendritic cells (DCs) and macrophages. Kidney DCs (orange) gather antigens (here represented in green as microbes) and transport them to draining lymph nodes to present them to specific T cells (red). Tissue-resident DCs can regulate activated T cells. Macrophages (violet) maintain tissue homeostasis, for example, by removing apoptotic cells. During infection, they may combat microbes by phagocytosis.

Figure 2.

Role of renal DCs and macrophages in selected kidney diseases. (A) Inflammasome activation in DCs and macrophages results from intratubular crystal formation, which is a consequence of the high osmolarity in the medulla that favors crystal formation. The inflammasome is an intracellular multimeric enzyme complex that contains adaptor proteins and caspase 1, which proteolytically activates IL-1β, resulting in inflammation. (B) Ischemia reperfusion injury activates DCs to produce TNF and chemokines that attract and stimulate injurious immune effector cells. (C) Glomerular inflammation activates periglomerular DCs in the renal cortex. They capture and present deposited or filtered antigens to CD4 T helper cells and stimulate these cells with IL-12. T cells secrete IFN-γ and cause macrophages to produce injurious mediators, like TNF or nitric oxide (NO). DCs, dendritic cells; MΦ, macrophage.

Figure 3.

The renal mononuclear system. Two-photon microscopy image of the renal mononuclear phagocyte system visualized by transgenic reporter mice in which cells, which include DCs, macrophages, and monocytes, harboring the receptor CX₃CR1 express green fluorescent protein. Reprinted from A. R. Kitching, with permission.

Figure 4.

Immune response against urinary tract infection. (A) In bacterial pyelonephritis, ascending uropathogenic E. coli (green) is sensed by Toll-like receptor (TLR) -expressing kidney DCs positioned in the medulla adjacent to collecting ducts and tubules. Medullary DCs respond by secreting CXCL2 that attracts neutrophils to eliminate the bacteria. (B) In bacterial cystitis, resident Ly6C⁻ sentinel macrophages sense uropathogenic E. coli and start secreting chemokines to recruit circulatory neutrophils and Ly6C⁺ monocytes. The latter differentiates into Ly6C⁺ helper macrophages that release TNF as helper signal, which enables Ly6C⁻ sentinel macrophages to produce additional chemokines to guide neutrophils into the frontline of infection (the uroepithelium) to combat the bacteria. MIF, macrophage migration inhibitory factor.