Resident Macrophages in Cystic Kidney Disease

Abstract

Interstitial inflammation is an important feature of cystic kidney disease. Renal macrophages are the most well-studied inflammatory cell in the kidney, and their involvement in cyst formation has been reported in different animal models and patients with cystic kidney disease. Originally, it was believed that renal macrophages were maintained from a constant supply of bone marrow-derived circulating monocytes, and could be recruited to the kidney in response to local inflammation. However, this idea has been challenged using fate-mapping methods, by showing that at least two distinct developmental origins of macrophages are present in the adult mouse kidney. The first type, infiltrating macrophages, are recruited from circulating monocytes and gradually develop macrophage properties on entering the kidney. The second, resident macrophages, predominantly originate from embryonic precursors, colonize the kidney during its development, and proliferate in situ to maintain their population throughout adulthood. Infiltrating and resident macrophages work together to maintain homeostasis and properly respond to pathologic conditions, such as AKI, cystic kidney disease, or infection. This review will briefly summarize current knowledge of resident macrophages in cystic kidney disease.

Figure 1.

The origins of macrophages in kidney. Two types of macrophages are present in the adult mouse kidney. Resident macrophages predominantly originate from embryonic precursors, migrate into the kidney during early development, and are maintained in the kidney through local proliferation. Infiltrating macrophages are derived from monocyte precursors in the bone marrow, and are recruited to the kidney in response to local inflammation. The dashed arrow indicates a limited but continuous contribution of monocyte-derived cells to the resident-macrophage pool in adult mouse kidneys.

Figure 2.

Proposed functions of resident macrophages during cyst formation and expansion. Multiple processes occur during cyst formation and expansion, including increased epithelial proliferation and apoptosis, interstitial inflammation, increased extracellular matrix deposition and renal fibrosis, and vasculature abnormalities. Resident macrophages may be involved in controlling several of these processes directly or indirectly. It has been proposed that resident macrophages can promote cystic epithelial proliferation by secretion of cytokines and phagocytosis of apoptotic epithelial cells. Also, renal-resident macrophages may drive interstitial myofibroblast activation and proliferation, leading to increased extracellular matrix deposition and renal fibrosis. Resident macrophages may serve as “first responders” in the kidney and control the accumulation and effector function of other immune cells, such as neutrophils, infiltrating macrophages, and T cells, to indirectly regulate cyst formation. Finally, renal resident macrophages may also regulate vasculature abnormalities through their proposed proangiogenic functions. The inset indicates the reciprocal communication between resident macrophages and the cilia mutant epithelium via mb-CSF1/CSF-1R. ECM, extracellular matrix; mb-CSF1, membrane-bound colony-stimulating factor-1; RM, resident macrophages; IM, infiltrating macrophages.