Chang Tzu-Hsuan, Cardona Gloria Yamel, Hellmann Margareta J, Richardo Timmy, Greve Carsten Leo, Le Roy Didier, Roger Thierry, Bork Francesca, Bugl Stefanie, Jakob Johanna, Sonnberger Johannes, Kasper Lydia, Hube Bernhard, Pusch Stefan, Gow Neil A R, Sørlie Morten, Tøndervik Anne, Moerschbacher Bruno M, Weber Alexander N R
Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany.
Institute for Biology and Biotechnology of Plants, University of Münster, Münster, Germany.
Front Immunol. 2025 Mar 3;16:1497174. doi: 10.3389/fimmu.2025.1497174. eCollection 2025.
Chitin is a highly abundant polysaccharide in nature and is linked to immune recognition of fungal infections and asthma in humans. Ubiquitous in fungi and insects, chitin is absent inmammals and plants and, thus, represents a microbeassociatedmolecular pattern (MAMP). However, highly polymeric chitin is insoluble, which potentially hampers recognition by host immune sensors. In plants, secreted chitinases degrade polymeric chitin into diffusible oligomers, which are "fed to" innate immune receptors and co-receptors. In human and murine immune cells, a similar enzymatic activity was shown for human chitotriosidase (CHIT1), and oligomeric chitin is sensed via an innate immune receptor, Toll-like receptor (TLR) 2. However, a complete system of generating MAMPs from chitin and feeding them into a specific receptor/co-receptor-aided sensing mechanism has remained unknown in mammals.
The effect of the secreted chitinolytic host enzyme, CHIT1, on the TLR2 activity of polymeric chitin preparations from shrimps, house dust mites and the fungal pathogen Candida albicans was assessed in vitro using cell lines and primary immune cells. Moreover, the regulation of CHIT1 was analyzed.
Here, we show that CHIT1 converts inert polymeric chitin into diffusible oligomers that can be sensed by TLR1/TLR2 co-receptor/receptor heterodimers, a process promoted by the lipopolysaccharide binding protein (LBP) and CD14. Furthermore, we observed that is induced via the b-glucan receptor Dectin-1 upon direct contact of immortalized human macrophages to the fungal pathogen , whereas the defined fungal secreted aspartyl proteases, Sap2 and Sap6, from were able to degrade CHIT1 .
Our study shows the existence of an inducible system of MAMP generation in the human host that enables contact-independent immune activation by diffusible MAMP ligands with a striking similarity to the plant kingdom. Moreover, this study highlights CHIT1 as a potential therapeutic target for TLR2-mediated inflammatory processes that are fueled by oligomeric chitin.
几丁质是自然界中含量极为丰富的多糖，与人类真菌感染和哮喘的免疫识别相关。几丁质在真菌和昆虫中普遍存在，在哺乳动物和植物中不存在，因此，它代表一种微生物相关分子模式（MAMP）。然而，高度聚合的几丁质是不溶性的，这可能会妨碍宿主免疫传感器的识别。在植物中，分泌的几丁质酶将聚合几丁质降解为可扩散的寡聚体，这些寡聚体被“提供给”先天免疫受体和共受体。在人类和小鼠免疫细胞中，人几丁质三糖酶（CHIT1）表现出类似的酶活性，并且寡聚几丁质通过先天免疫受体Toll样受体（TLR）2被感知。然而，在哺乳动物中，从几丁质产生MAMPs并将它们输入特定受体/共受体辅助传感机制的完整系统仍然未知。
使用细胞系和原代免疫细胞在体外评估分泌的几丁质分解宿主酶CHIT1对来自虾、屋尘螨和真菌病原体白色念珠菌的聚合几丁质制剂的TLR2活性的影响。此外，分析了CHIT1的调节。
在这里，我们表明CHIT1将惰性聚合几丁质转化为可被TLR1/TLR2共受体/受体异二聚体感知的可扩散寡聚体，这一过程由脂多糖结合蛋白（LBP）和CD14促进。此外，我们观察到，永生化人类巨噬细胞与真菌病原体直接接触后，β-葡聚糖受体Dectin-1可诱导CHIT1，而白色念珠菌分泌的特定天冬氨酸蛋白酶Sap2和Sap6能够降解CHIT1。
我们的研究表明，人类宿主中存在一种可诱导的MAMP产生系统，该系统能够通过可扩散的MAMP配体实现不依赖接触 的免疫激活，这与植物界有着惊人 的相似性。此外，本研究强调CHIT1作为TLR2介导的由寡聚几丁质引发的炎症过程的潜在治疗靶点。
