Although the M1 and M2 phenotypes are poorly understood, monocyte proinflammatory activation clearly is linked to NF-κB–mediated transcription of multiple innate immune genes. Activation of monocyte NF-κB by both pathogens and tissue damage involves TLR4 (see figure 1). This receptor responds to endotoxin released by certain bacteria (e.g., lipopolysaccharide [LPS]) as well as to HMGB1. Proinflammatory gene induction also is amplified by cytokine– receptor-activated release of HMGB1 that further contributes to innate immune gene induction.
