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. 2019 Oct 10;20(20):5023. doi: 10.3390/ijms20205023

Figure 5.

Figure 5

MTX inhibits HMGB-1/RAGE interaction. HMGB1 released by activated immune cells (macrophages, monocytes, and dendritic cells) or by injured cells acts as an important mediator of inflammation or alarmin. HMGB-1 activates cells through the engagement of multiple surface receptors including TLR2, TLR4, and RAGE. Downstream signaling of HMGB1 is mediated by a number of adaptor proteins, which converge through pathways involving mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) and transcriptional regulator, p53 pathways (Weber et al. 2015). HMGB-1 signaling through RAGE promotes maturation of immune cells, chemotaxis and release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8). MTX can bind to the RAGE binding domains of HMGB1 and inhibits the interaction between HMGB1 and its receptor RAGE, thus inhibiting the development of inflammatory responses. Binding of MTX to part of the RAGE-binding region in HMGB1 may be significant for the anti-inflammatory effect of MTX.