Figure 6:

Proposed mechanism for how MDSC utilise the regulatory factor, HMGB1, to control their effector functions depending on the environmental need after binding to the receptor TLR4. (a) Conventional phagocytes inhibit mTOR through the binding of HMGB1 to TLR4 (and other receptors like TLR2 and RAGE), allowing for the fusion of the lysosome to the autophagosome and subsequent killing of the bacteria. (b) M.tb-infected MDSC (likely found predominantly at the site of disease) on the other hand, increase the production of mTOR, thereby inhibiting the autophagy process and prohibiting the lysosome fusion to the autophagosome, harbouring the bacteria from killing mechanisms. Pro-inflammatory cytokines, like IL-6, produced during this process induce expansion of MDSC. (c) Uninfected MDSC (likely found predominantly in circulation) make use of HMGB1 in an alternate manner to induce autophagy within the cells. The induction of autophagy prolongs the survival of these cells while limiting their suppressive potential.