Figure 1. Innate immune responses to S. aureus during skin and bone infection.

(A) Left panel: S. aureus infects skin after breaching the epithelial layers. Keratinocytes and skin-resident macrophages produce inflammatory mediators that promote neutrophil responses. Middle panel: Neutrophils are recruited to the skin where they phagocytose bacteria, undergo degranulation, and produce extracellular traps that aid in bacterial killing. Right panel: S. aureus infection is contained by abscess formation. Live and dead neutrophils and bacteria are found within the abscess. The abscess becomes encapsulated with fibrous material and surrounded by macrophages. (B) Bone remodeling activities of osteoblasts and osteoclasts are altered following interactions between innate immune receptors and S. aureus. In osteoblasts, TLR2 recognition of extracellular S. aureus leads to production of AMPs, TLR9 detection of bacterial CpG DNA in the endosome induces an antibacterial ROS response, and NOD2 sensing of cytoplasmic S. aureus occurs following escape from the endosome. The culmination of osteoblastic innate recognition results in production of pro-inflammatory cytokines, such as TNFα, IL-1, and IL-6. These cytokines allow osteoblasts to favor increased production of RANKL and decreased release of the RANKL inhibitory cytokine OPG. The increased RANKL:OPG ratio and pro-inflammatory cytokine production have a net effect to enhance osteoclast differentiation. However, OB activation and the effects of staphylococcal toxins may also result in osteoblast cell death through apoptosis and necrosis. RANKL production allows for enhanced differentiation of osteoclast precursors. Pro-inflammatory cytokines such as TNFα and IL-1 can signal directly onto osteoclast precursors to increase osteoclast survival and bone resorption activity. Osteoclast expression and ligation of TLR2 has been shown to allow for the further differentiation down the osteoclast lineage, however this occurs only in cells that have first been stimulated with RANKL. Whether or not S. aureus can invade osteoclasts or activate endosomal or cytoplasmic PRRs remains to be determined.