Abstract
Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease.Authors SummaryChitin is the second most abundant polysaccharide in nature after cellulose and an essential component of the cell wall of all fungal pathogens. The discovery of human chitinases and chitinase-like binding proteins indicates that fungal chitin is recognised by cells of the human immune system, shaping the immune response towards the invading pathogen. We show that three immune cell receptors– the mannose receptor, NOD2 and TLR9 recognise chitin and act together to mediate an anti-inflammatory response via secretion of the cytokine IL-10. This mechanism may prevent inflammation-based damage during fungal infection and restore immune balance after an infection has been cleared. By increasing the chitin content in the cell wall pathogenic fungi may influence the immune system in their favour, by down-regulating protective inflammatory immune responses. Furthermore, gene mutations and dysregulated enzyme activity in the described chitin recognition pathway are implicated in inflammatory conditions such as Crohn's Disease and asthma, highlighting the importance of the discovered mechanism in human health.
Highlights
Chitin is a robust b-1,4-linked homopolymer of N-acetylglucosamine (GlcNAc) and is an essential polysaccharide of the cell wall of all fungal pathogens
We investigated the immune regulatory ability of ultrapure fungal chitin as a pathogen-associated molecular patterns (PAMPs) and describe several classes of immune receptors that are involved in chitin recognition (Fig. 9)
We show that fungal chitin acts as a concentration- dependent stimulus of pro- and anti-inflammatory cytokine secretion in vitro and in vivo
Summary
Chitin is a robust b-1,4-linked homopolymer of N-acetylglucosamine (GlcNAc) and is an essential polysaccharide of the cell wall of all fungal pathogens. It is absent in humans but is found in the skeletal elements in oomycetes, insects, crustaceans and parasitic nematodes [1,2,3,4]. The chitin content of the fungal cell wall increases in response to b-1,3 glucan damage, for example as inflicted by echinocandin antifungal drug treatment [7]. Recent work has identified additional chitin binding proteins, such as RegIIIg (HIP/PAP), a C-type lectin secreted by Paneth cells in the small intestine that binds peptidoglycan from Gram-positive bacteria [12], and FIBCD1, a high affinity receptor for chitin and chitin fragments that is highly expressed in the gastrointestinal tract [9]
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