Fig. 6

Working model of metabolic risk factor-induced two-way stimulatory immune checkpoint amplification and systemic/tissue inflammation. Metabolic risk factors, such as HHcy, uremic toxins, and other RF,, stimulate two-way stimulatory immune checkpoint amplification in TC, APC (MC), and possibly in PL via MADS recognition. In response to metabolic RF stimulation, metabolic sensors mediate TC activation via MAPK/NF-κB/calcineurin pathway, APC inflammation via STAT3MAPK/NF-κB pathway, MC differentiation via DNA hypomethylation, and possibly sCD40L production in PL via MAPK/NF-κB activation. TC activation and APC inflammation finally result in inflammatory cytokine production and systemic/tissue inflammation. Words in red emphasize our newly proposed signal pathway. Abbreviation: APC antigen present cell, HHcy hyperhomocysteinemia, MC monocyte, MAPK mitogen-activated protein kinase, MADS metabolism-associated danger signal, NF-κB nuclear factor κB, RF risk factor, PL platelet, STAT3 signal transducers and activator of transcription-3, sCD40L soluble CD40 ligand, TC T cell