On Feb 20, 2014,researchers at Xiaoming Gao’s group published an article entitled “Soluble Calreticulin Induces Tumor Necrosis Factor-α (TNF-α) andInterleukin (IL)-6 Production by Macrophages through Mitogen-Activated ProteinKinase (MAPK) and NFκB Signaling Pathways” in InternationalJournal of Molecular Sciences。
They have recently reported that soluble calreticulin(CRT) accumulates in the sera of patients with rheumatoid arthritis or systemiclupus erythematosus. Moreover, following self-oligomerization, solublerecombinant CRT (rCRT) polypeptides exhibit potent immunostimulatory activitiesincluding macrophage activation in vitro andantibody induction in vivo. Thisstudy was designed to further investigate the underlying molecular mechanismsfor soluble CRT-induced macrophage activation. Treatment of murine macrophageswith oligomerized rCRT (OrCRT) led to (i) TNF-α and IL-6 transcription and proteinexpression without affecting intracellular mRNA stability; and (ii) IκBαdegradation, NFκB phosphorylationand sustained MAPK phosphorylationin cells. Inhibition of IKK and JNK in macrophages substantially abrogated productionof TNF-α and IL-6 induced by orCRT, while ERKsuppression only reduced IL-6 expressionin parallel experiments. In vitro,fucoidan, a scavenger receptor A (SRA)-specific ligand, significantly reducedthe uptake of FITC-labeled orCRT by macrophages and subsequent MAPK and NFκB activation, thereby suggestingSRA as one of the potential cell surface receptors for soluble CRT. Together,these data indicate that soluble CRT in oligomerized form could play apathogenic role in autoimmune diseases through induction of pro-inflammatorycytokines (e.g., TNF-α and IL-6) by macrophages via MAPK-NFκB signaling pathway.
Cuicui Duo and Dr.Fangyuan Gong are the first authors of the paper. Contributing author are Xiaoyan He, Yanmei Li, Junwang and Jinping Zhang. Prof. Xiaoming Gao is the correspondingauthor of the paper. This study was supported by grants from the Program forChangjiang Scholars and Innovative Research Team PCSIRT (IRT1075), NationalFoundation of Nature Science of China (31370908/31070781/31200649), CollegiateNatural Science Fund of Jiangsu Province (12KJB310017/12KJA140001).