There is much speculation that HMGB1 does not act alone in the triggering of receptor activation. Proof of this concept was provided by Tian et al. who demonstrated that HMGB1-DNA complexes activate TLR9 signaling (64) . HMGB1 involvement in TLR9 activation appears to be mediated by HMGB1-DNA complexes rather than HMGB1 alone. While HMGB1-DNA complex stimulation of TLR9 is involved in maturation of immune cells and cytokine secretion (64, 65) , there is some evidence that these complexes may also suppress the immune response in some cell types (66) . In addition to the HMGB1-DNA interactions that activate TLR9, HMGB1 interactions with other cytokines such as IL-1β, IFNγ, and TNFα lead to an increased pro-inflammatory response compared with HMGB1 stimulation alone (67) . Ultimately, whether other interactions or modifications of HMGB1 are required for pattern recognition receptor binding or activation is uncertain.