MyD88-Syk axis is a critical determinant for inflammatory response in macrophages

Inhibition of Syk or MyD88 decreased generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and consequent ROS/RNS-induced phagocytic activity in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Syk inhibition downregulated expression of ROS/RNS-generating enzymes by inhibiting the nuclear factor-kappa B (NF-kappa?B) signaling pathway and phagocytic activity by suppressing suppressor of cytokine signaling 1 (SOCS1) via its nitration in the LPS-stimulated RAW264.7 cells. Inhibition of ROS/RNS generation suppressed SOCS1 nitration, leading to a decrease in the phagocytic activity. Syk was activated by the interaction with MyD88, and the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88 was critical for interaction and consequent activation of Syk in macrophages. Src activated MyD88 by phosphorylation at Y58 via the Src kinase domain. Moreover, LPS-induced formation of filamentous actin (F-actin) and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation induced Src activation. Conclusivley, these results suggest that the MyD88-Syk axis plays a pivotal role in macrophage-mediated inflammatory responses by inducing ROS/RNS generation and phagocytic activity via activation of Src and its upstream stimulators, F-actin and Rac1.