Podocytes Regulate Neutrophil Recruitment by Glomerular Endothelial Cells via IL-6–Mediated Crosstalk

Abstract

Stromal cells actively modulate the inflammatory process, in part by influencing the ability of neighboring endothelial cells to support the recruitment of circulating leukocytes. We hypothesized that podocytes influence the ability of glomerular endothelial cells (GEnCs) to recruit neutrophils during inflammation. To address this, human podocytes and human GEnCs were cultured on opposite sides of porous inserts and then treated with or without increasing concentrations of TNF-α prior to addition of neutrophils. The presence of podocytes significantly reduced neutrophil recruitment to GEnCs by up to 50% when cultures were treated with high-dose TNF-α (100 U/ml), when compared with GEnC monocultures. Importantly, this phenomenon was dependent on paracrine actions of soluble IL-6, predominantly released by podocytes. A similar response was absent when HUVECs were cocultured with podocytes, indicating a tissue-specific phenomenon. Suppressor of cytokine signaling 3 elicited the immunosuppressive actions of IL-6 in a process that disrupted the presentation of chemokines on GEnCs by altering the expression of the duffy Ag receptor for chemokines. Interestingly, suppressor of cytokine signaling 3 knockdown in GEnCs upregulated duffy Ag receptor for chemokines and CXCL5 expression, thereby restoring the neutrophil recruitment. In summary, these studies reveal that podocytes can negatively regulate neutrophil recruitment to inflamed GEnCs by modulating IL-6 signaling, identifying a potential novel anti-inflammatory role of IL-6 in renal glomeruli.

The effect of hydroxy safflower yellow A on coronary heart disease through Bcl‑2/Bax and PPAR‑γ

“…IL-6 and other pro-inflammatory cytokines are able to regulate the synthesis of coronary heart disease and IL-6 is fundamental to this process (15). Similar to CRP, the imbalance of IL-6 may influence vary diseases (5). In atherosclerosis, IL-6 primarily acts on blood vessel endothelium, causing it to be impaired and therefore activating a series of inflammatory responses (5), which leads to coronary atherosclerotic cardiomyopathy or the conversion of stable coronary heart disease to unstable (15).…”

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IL-6 Trans-Signaling Drives Murine Crescentic GN

“…36 Second, systemic effects of IL-6 on the immune system 34 may exacerbate renal disease, whereas there are well-documented instances of intrarenal IL-6 production, for example by podocytes, mediating anti-inflammatory effects. 37 Third, potential antiinflammatory IL-6 effects exerted by classic signaling may be offset by proinflammatory trans-signaling of IL-6.…”

The Janus Faces of IL-6 in GN

“…9 More recently, using an in vitro model, podocyte release of IL-6, again signaling via SOCS3, was shown to mediate an anti-inflammatory effect on microvascular glomerular endothelial cells (but not umbilical vascular endothelial cells), inhibiting TNF-mediated neutrophil recruitment and transmigration. 10 These in vivo and in vitro data demonstrate the complex duality of IL-6 action.…”