Phagocytosis-mediated M1 activation by chitin but not by chitosan

Abstract

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.

The fungal ligand chitin directly binds TLR 2 and triggers inflammation dependent on oligomer size

“…Since other PRR (e.g., TLR9 or NOD2) were equally proposed as chitin receptors (e.g., )—but not confirmed by molecular studies or direct binding—our study now for the first time provides conclusive experimental evidence for TLR2 as a primary chitin immune receptor. TLR2 seems to cooperate with TLR1 in agreement with , but possibly an additional receptor contributes to full activation. Our results provide a missing molecular link between fungal infection and the previously observed dependence on TLR2 in murine fungal infection models and, importantly, in patients with the functional rs5743708 (p.753RQ) TLR2 allele .…”

In silicoapproaches for enhancing retrieval analysis as a source for discovery of implant reactivity‐related mechanisms and biomarkers

“…In summary, our overall in silico analysis suggested that CD68 and its chitin‐related co‐expression signature may be particularly involved in in vivo M1/M2 macrophage polarization in chitin‐like responses that may control the extent of inflammatory cell recruitment and post‐inflammatory remodeling of peri‐implant tissues and thereby may predetermine the likelihood of subsequent aseptic loosening.…”

“…Chitin oligomers released by endochitinases induce the host defense‐related activation of polarized macrophages, which is dependent on the particle size and shape . Non‐phagocytosable (larger than a macrophage) chitin particles may induce M2 activation aimed at tissue repair.…”

“…Chitin oligomers released by endochitinases induce the host defense-related activation of polarized macrophages, which is dependent on the particle size and shape. 22,26 Non-phagocytosable (larger than a macrophage) chitin particles may induce M2 activation aimed at tissue repair. In contrast, phagocytosable (<10 μ) chitin particles not only may induce M1 macrophages, which are aimed to kill intracellular pathogens, but may also damage the surrounding tissues.…”

“…In contrast, phagocytosable (<10 μ) chitin particles not only may induce M1 macrophages, which are aimed to kill intracellular pathogens, but may also damage the surrounding tissues. 22 Considering a similar size/shaperelated modification of the implant debris-related phagocytosis and subsequent innate responses, 10,11,27 it is plausible to suggest that the implant-related host response may mimic evolutionarydeveloped mammalian responses to the chitin-containing pathogens. Consequently, biomedical knowledge on chitin-induced PAMPs may help clarify the implant-related DAMPs.…”