Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Abstract

S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-γ expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-γ production, and Pan02-S100A8/A9 cells further increased the number of IFN-γ+ NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-γ production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02-S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9–RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity.

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…101), which is overexpressed in patients with type 2 diabetes 102 . This protein has been shown to stimulate a local inflammatory response via interaction with RAGE 103 , leading to activation of mitogen-activated protein kinases (MAPKs), NF-κB and apoptosis 104,105 . Similarly, MAPKs (such as p38 MAPK, MAPK1, MAPK3, MAPK8 and MAPK10) are activated by high glucose levels in human Schwann cell cultures 106 ; p38 is of particular interest, as it is a negative regulator of Schwann cell differentiation and myelination 107 .…”

S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis

“…S100A8 is specific for cells of myeloid origin such as granulocytes, monocytes, and macrophages, but it is not detected in resident tissue macrophages123456. S100A8 is overexpressed in various inflammatory and infectious pathologies including rheumatoid arthritis, Crohn’s disease, psoriasis, cystic fibrosis, Pseudomonas aeruginosa keratitis, and autoinflammatory diseases78910111213. S100A8 and S100A9 may have different functions in mice and humans; however, Ca 2+ can induce formation of stable heterodimers of S100A8/S100A9.…”

Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation

“…Многие исследования пока-зали, что белки S100 оказывают воздействие на эффек-торные клетки воспаления, иммунной системы, эндо-и эпителиальные клетки, действуя аналогично цитокинам и приводя к развитию локального воспалительного ответа [45]. Недавно найден новый механизм, посредством кото-рого происходит активация NK-клеток через S100A8/A9-RAGE-сигнальный путь и который поможет по-новому взглянуть на взаимосвязь in vivo между воспалением и естественным иммунитетом [48].…”