Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

摘要

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation, inflammation, and fibrosis. Macrophages infiltrate cystic kidneys, but the role of these and other inflammatory factors in disease progression are poorly understood. Here, we identified macrophage migration inhibitory factor (MIF) as an important regulator of cyst growth in ADPKD. MIF was upregulated in cyst-lining epithelial cells in polycystin-1–deficient murine kidneys and accumulated in cyst fluid of human ADPKD kidneys. MIF promoted cystic epithelial cell proliferation by activating ERK, mTOR, and Rb/E2F pathways and by increasing glucose uptake and ATP production, which inhibited AMP-activated protein kinase signaling. MIF also regulated cystic renal epithelial cell apoptosis through p53-dependent signaling. In polycystin-1–deficient mice, MIF was required for recruitment and retention of renal macrophages, which promoted cyst expansion, and Mif deletion or pharmacologic inhibition delayed cyst growth in multiple murine ADPKD models. MIF-dependent macrophage recruitment was associated with upregulation of monocyte chemotactic protein 1 (MCP-1) and inflammatory cytokine TNF-α. TNF-α induced MIF expression, and MIF subsequently exacerbated TNF-α expression in renal epithelial cells, suggesting a positive feedback loop between TNF-α and MIF during cyst development. Our study indicates MIF is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for further exploration of MIF as a therapeutic target for ADPKD. Keywords: Genetics, Inflammation, NephrologyIntroductionAutosomal dominant polycystic kidney disease (ADPKD) is an inherited disease characterized by formation and progressive growth of innumerous cysts and is associated with renal interstitial inflammation and fibrosis. ADPKD is caused by mutations in PKD1 and PKD2 , genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively (1). Multiple signaling pathways have been identified in regulating cystic renal epithelial cell proliferation and apoptosis, and targeting these pathways delays cyst growth in animal models of PKD (2–4). Interstitial inflammation, which has been consistently reported in human and animal models of PKD, also regulates cyst growth and is associated with functional impairment. The selective depletion of macrophages in kidneys of Pkd1 conditional KO mice and congenital polycystic kidney ( cpk) mice caused a significantly lower cystic index, reduced proliferation of cyst-lining cells, and improved renal function (5, 6). However, the mechanisms promoting recruitment of macrophages to pericystic and interstitial sites within cystic kidneys, and the specific roles macrophages and other infiltrating inflammatory cells play in cystogenesis, have not been defined.Macrophage migration inhibitory factor (MIF) as a pleiotropic proinflammatory cytokine (7), possessing tautomerase activity, plays an important role in the recruitment of innate and adaptive immune cells to sites of inflammation (8). MIF was originally identified as a soluble factor in the culture medium of activated T lymphocytes that inhibited the random migration of macrophages. In addition to T lymphocytes, MIF is also expressed and secreted by other cell populations, including macrophages/monocytes (9, 10), endothelial cells (ECs) (11), epithelial cells (12), smooth muscle cells (13), synovial fibroblasts (14), and anterior pituitary cells (14). In adults, the predominant sites of MIF expression are the proliferating and differentiating epithelial linings of various organs (15). The broad expression of MIF suggests that it is involved in a wide array of physiological and pathophysiological processes.MIF plays a critical pathogenic role in kidney diseases through mechanisms involving the innate and adaptive immune systems; the induction of cytokines, chemokines, and adhesion molecules; and interactions with glucocorticoids and the hypothalamic-pituitary–adrenal axis (16). High MIF production is found in human and experimental kidney disease and contributes to macrophage and T cell accumulation, as well as progressive renal injury (16). Upregulation of MIF was also reported in the kidney tissue of IgA nephropathy patients, compared with healthy controls and patients with anti-neutrophil cytoplasmic antibody–associated (ANCA-associated) glomerulonephritis (17). The functional importance of MIF in kidney disease is demonstrated by the findings that treatment with a neutralizing anti-MIF antibody prevents or reverses renal injury in crescentic anti-GBM glomerulonephritis (18). In addition, mice null for MIF are protected against immune-mediated lupus nephritis (19).MIF is considered an important therapeutic target for treating inflammatory diseases, autoimmune diseases, neoplasia, and cancer. MIF regulates the cellular activities through transcriptional regulation of inflammatory gene products; modulation of cell proliferation, differentiation,