Chitin oligomers induce atypical NLRP3 inflammasome activation and innate immune training

Abstract

Chitin is a highly abundant poly- N-acetyl-glucosamine (GlcNAc) and linked to immune recognition of fungal infections and asthma in humans. Ubiquitous in fungi and insects, in mammals and plants chitin represents a microbe-associated molecular pattern (MAMP) and whereas highly polymeric chitin is insoluble and immunologically inert, soluble chitin oligomers of 6 to 15 GlcNAc activate immediate pro-inflammatory cytokine release via TLR2 in human immune cells. However, TLR2 ligands do not the most typical activators of the NLRP3 inflammasome pathway or innate immune training, a phenomenon of long-term immunological remodeling. Here we show that especially 16-20 GlcNAc long chitin oligomers activate NLRP3-dependent IL-1{beta} and IL-18 release in human myeloid immune cells in an atypical, phagocytosis-dependent manner. Moreover, phagocytosis and methyl transferase activity were essential for innate immune training, by which the same chito-oligomer-training enhanced TNF release in primary murine and human immune cells. Collectively, this suggests that oligomer length impacts on the immune features of chitin which can be customized using glycan assembly.