Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-α-mediated podocyte loss.
Loss of function mutations in the α3 or α4 chain of type IV collagen cause Alport nephropathy, characterized by progressive glomerulosclerosis. While studying the mechanisms that determine disease progression, we found that the evolution of kidney disease in Col4a3-deficient mice was associated with an influx of immune cell subsets including nonactivated macrophages. This suggested that intrarenal inflammation might accelerate Alport nephropathy. A possible mechanism might be the well-known enhancement of immune recognition by bacterial products. We found that exposure to bacterial endotoxin from 4 to 6 weeks of age did not affect disease progression, whereas an equipotent dose of cytosine-guanine (CpG)-DNA, a synthetic mimic of bacterial DNA, accelerated all aspects of Alport nephropathy and reduced the overall lifespan of Col4a3-deficient mice. This effect was associated with a significant increase of renal CD11b+/Ly6C(hi) macrophages, intrarenal production of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, interleukin-12, and CXCL10, and loss of podocytes. TNF-α was essential for acceleration of Alport nephropathy, as etanercept (a soluble TNF-α receptor) entirely abrogated the CpG-DNA effect. Thus, systemic exposure to CpG-DNA induces classically activated (M1) macrophages that enhance intrarenal inflammation and disease progression. Hence, factors that modulate the phenotype of renal macrophages can affect the progression of Alport nephropathy and, potentially, other types of chronic kidney diseases.
Ryu
Mi
M
Nephrologisches Zentrum, Medizinische Poliklinik der LMU, University of München, München, Germany.
Kulkarni
Onkar P
OP
Radomska
Ewa
E
Miosge
Nicolai
N
Gross
Oliver
O
Anders
Hans-Joachim
HJ
D000818:Animals; D001324:Autoantigens / Q000235:genetics; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics; D018899:CpG Islands; D004269:DNA, Bacterial / Q000235:genetics / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D050199:Podocytes / Q000276:immunology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D001324:Autoantigens; D024141:Collagen Type IV; D004269:DNA, Bacterial; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C057112:type IV collagen alpha3 chain