Pattern recognition and renal defence in crescentic glomerulonephritis.
Chavele et al. studied the role of the mannose receptor (MR) in crescentic nephritis. The accelerated nephrotoxic model of glomerulonephritis was induced on both wild-type (WT) and MR-deficient mice. The mice lacking the MR showed a markedly altered phenotype. They were largely protected against the development of glomerulonephritis with less affected glomeruli, less proteinuria and much better renal function when compared to the WT mice. Whilst more infiltrating macrophages were present in the WT animals, there was no difference in the deposition of sheep and mouse immunoglobulins. To elucidate the mechanism of MR-mediated damage, the authors additionally performed a series of in vitro experiments. They show that the Fab portion of sheep immunoglobulins binds to MR binding domains. Interestingly, the MR seems to interact with FcR-mediated cellular reactions. When MR-deficient macrophages and mesangial cells were treated with immune complexes, the macrophages showed a significantly poorer oxygen burst when compared with WT cells. In line with this possible interaction between Fc-receptors and MR, co-localization of Fcã-receptors and MR was demonstrated on macrophages. Additionally, the authors observed that MR-deficient mesangial cells in culture proliferated more abundantly and showed a markedly increased rate of spontaneous apoptosis compared with WT cells. These findings led the authors to test whether this increased apoptosis could play a role in the suppression of glomerular inflammation. Indeed, TNF-á production by LPS-stimulated macrophages was markedly reduced in the presence or apoptotic cells. The anti-inflammatory effect of apoptotic mesangial cells was increased when MR-deficient macrophages were used instead of WT cells (Figure 1). Fig. 1 Proposed role for mannose receptor in crescentic glomerulonephritis. (A) IgG may bind to the Fc receptor with the Fc domain and to the mannose receptor with the Fab portion leading to an increased oxygen burst (left). If the mannose receptor is absent, the oxygen burst is decreased (right). (B) Absence of the mannose receptor leads to an increased proliferation and apoptosis of mesangial cells. These apoptotic cells induce a non-inflammatory macrophage phenotype with IL-10 and TGF-beta production (right). If the mannose receptor is present, mesangial cells proliferate less and are less apoptotic, and a pro-inflammatory macrophage phenotype with TNF-alpha production prevails.
Berger
Stefan P
SP
Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands. s.p.berger@lumc.nl
Daha
Mohamed R
MR
D000818:Animals; D005921:Glomerulonephritis / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D037181:Lectins, C-Type / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000502:physiology*; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism
D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011961:Receptors, Fc