The renal mononuclear phagocytic system

Abstract

The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.

Figure 1.

Ontogeny of the renal mononuclear phagocytic system of the mouse at steady state and during inflammation. At steady state, bone marrow–resident MDPs give rise to common dendritic cell precursors (CDPs) and pre-DCs. Pre-DCs circulate to the healthy kidney to generate CD103⁺ rMoPh and a proportion of the resident CD11b⁺ rMoPh. MDPs also give rise to circulating Ly-6C⁺ monocytes and Ly-6C⁻ monocytes, which act as additional precursors for resident CD11b⁺ rMoPh. During renal inflammation, large numbers of Ly6C⁺ (inflammatory) monocytes are released from the bone marrow in CCR2/CCL2-dependent fashion and enter the injured kidney along with a proportion of circulating Ly6C⁻ monocytes. Infiltrating Ly-6C⁺ monocytes serve as precursors for rMoPh with the characteristics of classically activated (M1) Mø and inflammatory DCs. Alternatively activated (M2) Mø arise from M1 Mø through reprogramming (plasticity). Additional work is required to determine whether M2 Mø or other inflammatory rMoPh develop directly from infiltrating Ly6C⁻ monocytes. The growth factor axes, Flt3L/CD135 and CSF-1/CD115, important in the development of rMoPh are also shown in the figure.

Figure 2.

Proposed model for plasticity of rMoPh during inflammation and repair. During inflammation, rMoPh are derived from both resident and infiltrating cells. The release of DAMPs provides a proinflammatory stimulus and activates rMoPh to produce injurious mediators such as TNFα. In the absence of ongoing injury, such rMoPh subsequently undergo an intrinsic phenotypic shift with upregulation of anti-inflammatory and reparative mediators such as hemeoxygenase-1 and wnt ligands. An anti-inflammatory and reparative phenotype may also be induced by uptake of apoptotic cells or exposure to IL-10 and other mediators. rMoPh and their precursors are exposed to renal-derived poietins (e.g., CSF-1 and granulocyte macrophage colony-stimulating factor), which can influence their differentiation and functional polarization.