Principles of extra- and intracellular chitin perception by mammalian pattern recognition receptors

几丁质是一种β-1,4-连接n -乙酰氨基葡萄糖（GlcNAc）的疏水性聚合物，在自然界中含量丰富，例如真菌的细胞壁，甲壳类动物和昆虫等节肢动物的外骨骼以及线虫。然而，几丁质并不存在于哺乳动物和植物中。在这些生物中，几丁质是一种典型的微生物相关分子模式（MAMP），几丁质通过模式识别受体（PRRs）介导的免疫反应激活证明了这一点。在人类中，随之而来的prr介导的炎症反应与真菌感染和过敏性哮喘有关。在初始暴露过程中，哺乳动物宿主通常会接触到高度聚合和不溶性形式的几甲壳素，例如室内尘螨的外骨骼碎片或白色念珠菌或新生念珠菌等病原真菌的细胞壁，这种聚合不溶性几甲壳素被认为是免疫惰性的。然而，我们之前的研究表明，在人类中，免疫细胞中对可溶性寡聚几丁质的感知是由toll样受体（TLR） 2介导的，而其他人的研究表明FIBCD1或LYSMD3参与上皮细胞。我们最近发现TLR2信号也使用LBP、CD14和TLR1，并且可以被宿主内几丁质酶CHIT1提供的弥散配体激活。这些新发现的感知途径与植物中的几丁质感知非常相似，在植物中，细胞表面受体CERK1及其共受体CEBiP检测宿主几丁质酶产生的几丁质低聚物。然而，哺乳动物CHIT1-TLR系统的结构-功能关系（如乙酰化程度和模式）和几丁质感知的调控有待系统的探索，以更好地理解和可能的靶向细胞外几丁质感知。此外，碳水化合物合成的最新进展为系统分析定制的非天然合成低聚物在哺乳动物系统中的激动和拮抗免疫调节特性提供了可能性。最后，在细胞内真菌病原体如新生C.的背景下，胞质内几丁质感应的有趣概念仍然开放，但对于理解细胞内真菌病原体引发的免疫反应可能至关重要。基于与其他联盟成员一起产生的初步数据，以及在该优先项目中可用的进一步合作伙伴关系和工具，这些开放的问题将在人类和小鼠细胞系统中得到解决，希望描绘出哺乳动物中决定几丁质细胞外和细胞内免疫刺激的“代码”。在第一个资助阶段获得的知识随后可用于解释和调节/预防壳基生物材料中的免疫反应，和/或用于专门构建具有特定免疫激动或-拮抗特性的材料。

Chitin, a hydrophobic polymer of β-1,4-linked N-acetylglucosamine (GlcNAc), is abundant in nature and can be found e.g. in the cell wall of fungi, the exoskeletons of arthropods such as crustaceans and insects, and nematodes. However, chitin does not exist in mammals and plants. In these organisms, chitin is a typical microbe-associated molecular pattern (MAMP), as evidenced by the existence of chitin-mediated activation of immune responses through pattern recognition receptors (PRRs). In humans the consequent PRR-mediated inflammatory responses have been associated with fungal infections and allergic asthma. During initial exposure, the mammalian host typically encounters chitin in a highly polymeric and insoluble form – e. g. fragments of the exoskeleton of house dust mites or the cell wall of pathogenic fungi like C. albicans or C. neoformans – and this polymeric insoluble chitin has been considered immunologically inert. However, we previously showed that in humans, sensing of soluble, oligomeric chitin is mediated by Toll-like receptor (TLR) 2 in immune cells, whereas work by others demonstrated FIBCD1 or LYSMD3 are involved in epithelial cells. We recently found that TLR2 signaling also employs LBP, CD14 and TLR1 and can be activated by diffusible ligands provided by the host endochitinase, CHIT1. These newly discovered sensing pathways are highly reminiscent of chitin perception in plants, where the cell-surface receptors CERK1 and its co-receptor CEBiP detect chitin oligomers generated by host chitinases. However, in the structure-function relationships (e.g. degree and pattern of acetylation) and the regulation of chitin sensing by the mammalian CHIT1-TLR system await systematic exploration for a better understanding and, possibly, targeting of extracellular chitin sensing. Moreover, recent advances in carbohydrate synthesis open the possibility for systematic analysis of custom-made, non-natural synthetic oligomers for agonistic and antagonistic immune-regulatory properties in mammalian systems. Finally, the intriguing notion of cytosolic chitin sensing in the context of intracellular fungal pathogens like C. neoformans remains open but could be vital for understanding immune responses triggered by intracellular fungal pathogens. Based on the preliminary data generated together with other consortium members and with further partnerships and tools available within this priority program, these open questions will be addressed in both human and murine cellular systems, hoping to delineate a ‘code’ of what determines extra- and intracellular immune stimulation by chitin in mammalia. The knowledge gained in the first funding phase could then be applied to explain and modulate/prevent immune reactions in the context of chito-based biomaterials and/or exploited to purpose-build materials with specific immune-agonistic or -antagonistic properties.