[No authors listed]
Chitin particles have been used to understand host response to chitin-containing pathogens and allergens and are known to induce a wide range of polarized macrophage activations, depending, at least in part, on particle size. Nonphagocytosable particles larger than a macrophage induce tissue repair M2 activation. In contrast, phagocytosable chitin microparticles (CMPs, 1-10 μm diameters) induce M1 macrophages that kill intracellular microbes and damage tissues. However, chitosan (deacetylated) microparticles (de-CMPs, 1-10 µm) induce poor M1 activation. Toll-like receptor 2 (TLR2) and associated coreceptors in macrophages appear to be required for the M1 activation. To understand the exact mechanism of phagocytosis-mediated M1 activation by chitin, we isolated macrophage proteins that bind to CMPs during early phagocytosis and determined that TLR1, TLR2, CD14, late endosomal/lysosomal adaptor MAPK and mechanistic target of rapamycin activator 1 (LAMTOR1), Lck/Yes novel tyrosine kinase (Lyn), and β-actin formed phagosomal CMP-TLR2 clusters. These proteins were also detected in TLR2 phagosomal clusters in macrophages phagocytosing de-CMPs, but at relatively lower levels than in the CMP-TLR2 clusters. Importantly, CMP-TLR2 clusters further recruited myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-1 receptor-containing adaptor protein (TIRAP) and phosphorylated Lyn, whereas neither the adaptors nor phosphorylated Lyn was detected in the de-CMP clusters. The results indicate that the acetyl group played an obligatory, phagocytosis-dependent role in the initiation of an integrated signal for TLR2-mediated M1 activation.
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