Figure 6

Hypothetical mechanism of alternative activation of macrophages in response to Staphylococcus aureus infection. Left panel – Staphylococcus aureus enters the macrophage through the Toll-like receptor 2 (TLR2)-dependent pathway that initiates nuclear factor kappa B (NFKB)-mediated temporal inflammatory response. Triggering receptor expressed on myeloid cells 1 (TREM1) synergizes with TLR2 that stimulates intracellular signals resulting in phagocytosis and production of proinflammatory cytokines. NFKB induces expression of co-stimulatory receptor tumor necrosis factor superfamily member 5 (CD40). After phagosomal escape into the cytosol Staphylococcus aureus peptidoglycan induces nucleotide-binding and oligomerization domain 2 (NOD2) expression that in turn triggers inflammation. The macrophage is induced to produce interleukin 4 (IL-4) and IL-13 as confirmed by our study. Right panel – hypothetical alternative activation pathway triggered by IL-4 and IL-13, likely a mechanism by which Staphylococcus aureus evades the host immune response. Alternatively activated macrophage produces anti-inflammatory IL-10, which inhibits classical macrophage activation. Caspase 1(CASP1); interleukin 4 receptor (IL-4R); interleukin 13 receptor (IL-13R); Janus kinase (JAK) and signal transducer and activator of transcription (STAT).