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Activated macrophages direct apoptosis and suppress mitosis of mesangial cells
J S Duffield1, L P Erwig, X Wei
1Centre for Inflammation Research, Department of Clinical Sciences, Royal Infirmary, University of Edinburgh, Edinburgh, United Kingdom. j.duffield@ed.ac.uk
Abstract:
During inflammation in the glomerulus, the complement of resident myofibroblast-like mesangial cells is regulated by mitosis and apoptosis, but the cellular mechanisms controlling the size of mesangial cell populations have remained obscure. Prompted by studies of development, we sought evidence that macrophages regulate mesangial cell number. Rat bone marrow-derived macrophages primed with IFN-gamma then further activated in coculture with LPS or TNF-alpha elicited a 10-fold induction of rat mesangial cell apoptosis and complete suppression of mitosis, effects inhibitable by the NO synthase inhibitors L-monomethyl arginine and L-N(6)-(1-iminoethyl) lysine dihydrochloride. Complete dependence upon macrophage-derived NO was observed in comparable experiments employing activated bone marrow macrophages from wild-type and NO synthase 2(-/-) mice. Nevertheless, when mesangial cells were primed with IFN-gamma plus TNF-alpha, increased induction by activated macrophages of mesangial apoptosis exhibited a NO-independent element. The use of gld/gld macrophages excluded a role for Fas ligand in this residual kill, despite increased expression of Fas and increased susceptibility to soluble Fas ligand exhibited by cytokine-primed mesangial cells. Finally, activated macrophages isolated from the glomeruli of rats with nephrotoxic nephritis also induced apoptosis and suppressed mitosis in mesangial cells by an L-monomethyl arginine-inhibitable mechanism. These data demonstrate that activated macrophages, via the release of NO and other mediators, regulate mesangial cell populations in vitro and may therefore control the mesangial cell complement at inflamed sites.
Insights
Activated macrophages regulate mesangial cell populations during inflammation. They induce apoptosis and suppress mitosis in these cells, primarily through nitric oxide (NO) release, impacting kidney health.
Area of Science:
- Immunology
- Nephrology
- Cell Biology
Background:
- Mesangial cell population size is crucial in glomerular inflammation but the regulatory mechanisms are unclear.
- Studies suggest a role for macrophages in modulating cell numbers during development.
Purpose of the Study:
- To investigate whether macrophages regulate mesangial cell number.
- To elucidate the cellular and molecular mechanisms involved in this regulation.
Main Methods:
- Co-culturing rat bone marrow-derived macrophages with mesangial cells.
- Utilizing nitric oxide (NO) synthase inhibitors and macrophages from NO synthase 2 knockout mice.
- Examining the role of Fas ligand and using macrophages from nephrotoxic nephritis models.
Main Results:
- Activated macrophages induced significant mesangial cell apoptosis and suppressed mitosis.
- Nitric oxide (NO) was identified as a key mediator, with effects inhibitable by NO synthase inhibitors.
- A NO-independent apoptotic pathway was observed under certain cytokine priming conditions.
- Activated macrophages from inflamed kidneys also regulated mesangial cell apoptosis and mitosis via an NO-dependent mechanism.
Conclusions:
- Activated macrophages, through NO and other mediators, control mesangial cell populations.
- This macrophage-mediated regulation is significant at inflamed sites within the glomerulus.
- Findings suggest a novel mechanism for controlling mesangial cell numbers in kidney inflammation.