Macrophage apoptosis in rat crescentic glomerulonephritis.
The fate of macrophages at the site of inflammation is unknown. We investigated this question in a macrophage-mediated model of crescentic glomerulonephritis in which macrophage accumulation is relatively stable despite the presence of high levels of local macrophage proliferation. Accelerated anti-glomerular basement membrane glomerulonephritis was induced in groups of six rats that were killed on day 1, 7, 14, or 21. Macrophage apoptosis was demonstrated in kidney sections by three methods: in situ terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nick end labeling (TUNEL) combined with ED1 antibody immunostaining of macrophages, ED1 immunostaining combined with classical nuclear morphology, and electron microscopy. Substantial macrophage apoptosis became evident on day 14 of the disease, following the appearance of high levels of macrophage proliferation. The parallel relationship between proliferation and apoptosis is the likely explanation for the stabilization of macrophage numbers within the inflamed kidney. A striking feature was that macrophage proliferation and apoptosis was largely restricted to areas of focal damage, such as in the development of glomerular crescents. Increasing levels of macrophage proliferation and apoptosis were evident as crescents developed from a cellular to a fibrocellular phenotype, with a dramatic reduction in both of these processes in the progression to a fibrotic phenotype, suggesting an important role for macrophage apoptosis in the resolution of fibrocellular crescents to an acellular fibrotic structure. In conclusion, this study has identified apoptosis as an important mechanism counterbalancing local proliferation in the regulation of macrophage accumulation at sites of inflammation. Indeed, apoptosis may be a central regulator of the progression and resolution of macrophage-mediated tissue injury.
Lan
H Y
HY
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Mitsuhashi
H
H
Ng
Y Y
YY
Nikolic-Paterson
D J
DJ
Yang
N
N
Mu
W
W
Atkins
R C
RC
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002467:Cell Nucleus / Q000473:pathology / Q000648:ultrastructure; D004249:DNA Damage; D005921:Glomerulonephritis / Q000473:pathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley