Inducing M2 polarization, a surprising function of HMGB1

HMGB1 is a multifunctional protein with main function of a DAMP molecule which binds to several receptors and subsequently triggers inflammatory responses. Macrophages are dynamic cells that play critical roles in the induction and resolution of inflammation. Activated macrophages are classified into inflammatory M1 and anti-inflammatory M2 phenotypes.

HMGB1 acts on RAGE and TLRs on the monocyte membrane to regulate macrophage polarization. Although HMGB1 is known to polarize monocytes into M1 macrophage phenotype, multiple studies reveal that HMGB1 also induce M2 macrophage differentiation. Son el al. showed that HMGB1 and C1q mediate M2 macrophage polarization via binding to RAGE and LAIR-1 complex. Shiau et al. reported that HCC-derived HMGB1 promotes autophagy-regulated M2 polarization of TAMs via the production of ROS in these cells through the TLR2/NOX2 axis. These findings provide insight into a therapeutic potential by targeting HMGB1-mediated M2 polarization for inhibiting immunosuppressive TAMs or attenuating inflammatory diseases including neuropathological disorders.