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Chemoattractants provoke monocyte adhesion to human mesangial cells and mesangial cell injury
H R Brady1, M D Denton, W Jimenez
1Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts.
Abstract:
Infiltration of glomerular mesangium by monocytes/macrophages is a prominent pathologic finding in many forms of glomerulonephritis (GN). While the mechanism(s) by which infiltration occurs is incompletely understood, monocyte adhesion to glomerular endothelial cells, provoked by inflammatory mediators, appears to be an important early step. In the present study, we assessed the influence of chemotactic peptides (C5a) and lipids (LTB4 and PAF) on adhesion of human monocytes and mesangial cells, to determine if mesangial cells (glomerular pericytes with smooth muscle properties) represent potential targets for adhesion of chemoattractant-activated monocytes following their diapedesis from the intravascular space. C5a and LTB4 provoked rapid (onset less than 1 min) monocyte-mesangial cell adhesion at nanomolar concentrations via actions with monocytes, while PAF was less potent in this regard. Monoclonal antibodies (mAb) were used to define the monocyte and mesangial cell adhesion molecules involved in these interactions. C5a- and LTB4-induced monocyte adhesion was inhibited (approximately 54%) by mAb against the common beta CD18 subunit of CD11/CD18 leukocyte integrins, while mAb against monocyte L-selectin was without effect. MAb against unique CD11 subunits were used to determine the relative contributions of different CD11/CD18 integrins. In this regard, adhesion was inhibited by mAb against CD11b (approximately 41%), and CD11c (approximately 23%), but not CD11a. MAb against mesangial cell ICAM-1 afforded approximately 27% reduction in adhesion, while mAb against VCAM-1, E-selectin, and P-selectin were without effect. GM-CSF, a cytokine generated by monocytes and mesangial cells, also provoked CD11/CD18-dependent adhesion, and primed monocytes to the actions of chemoattractants.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chemotactic peptides like C5a and LTB4 rapidly promote monocyte adhesion to mesangial cells via leukocyte integrins. This interaction is crucial for understanding monocyte infiltration in glomerulonephritis (GN).
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Monocyte/macrophage infiltration of the glomerular mesangium is characteristic of glomerulonephritis (GN).
- Monocyte adhesion to glomerular endothelial cells, triggered by inflammatory mediators, is a key early step in this infiltration process.
Purpose of the Study:
- To investigate the role of mesangial cells as targets for chemoattractant-activated monocyte adhesion.
- To determine the influence of chemotactic peptides (C5a, LTB4) and lipids (PAF) on monocyte-mesangial cell adhesion.
Main Methods:
- Assessed monocyte-mesangial cell adhesion using chemotactic peptides and lipids.
- Utilized monoclonal antibodies (mAbs) to identify involved adhesion molecules on monocytes and mesangial cells.
- Investigated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on adhesion.
Main Results:
- C5a and LTB4 induced rapid monocyte-mesangial cell adhesion at nanomolar concentrations, primarily through monocyte actions.
- Adhesion was significantly inhibited by mAbs against the CD18 subunit of leukocyte integrins (CD11/CD18), CD11b, and CD11c.
- Mesangial cell ICAM-1 partially reduced adhesion, while VCAM-1, E-selectin, and P-selectin had no effect.
- GM-CSF also induced CD11/CD18-dependent adhesion and primed monocytes.
Conclusions:
- Mesangial cells are potential targets for chemoattractant-activated monocyte adhesion.
- Leukocyte integrins (CD11/CD18), particularly involving CD11b and CD11c, are critical for monocyte-mesangial cell adhesion.
- ICAM-1 on mesangial cells plays a supporting role in this adhesion process.