Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing
Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing
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壳三糖苷酶 (CHIT1) 产生 MAMP 的跨界机制将来自真菌病原体和过敏原的寡聚几丁质输送到 TLR2 介导的先天免疫传感中
DOI：
10.1101/2022.02.17.479713
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发表时间：
--
期刊：
影响因子：
--
通讯作者：
Weber ANR
中科院分区：
文献类型：
--
作者：
Chang T-H;Cardona Gloria Y;Hellmann M;Greve C;Le Roy D;Kasper L;Hube B;Pusch S;Sorlie M;Tondervik A;Moerschbacher B;Weber ANR
甲壳素是自然界中含量丰富的多糖，与人类真菌感染和哮喘的免疫识别有关。甲壳素普遍存在于真菌和昆虫中，但在哺乳动物和植物中不存在，因此代表了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，这可能会阻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的几丁质降解成可扩散的低聚物，其被"喂养"先天免疫受体和共受体。在人类和小鼠免疫细胞中，人类壳三糖苷酶（CHIT 1）显示出类似的酶活性，并且寡聚几丁质通过先天免疫受体Toll样受体（TLR）2感知。然而，一个完整的系统，产生MAMPs从甲壳素和喂养他们到一个特定的受体/共受体辅助传感mechanism.MethodsThe分泌的几丁质分解宿主酶，CHIT 1，对聚合甲壳素制剂从虾，屋尘螨和真菌病原体白色念珠菌的TLR2活性的影响仍然是未知的在哺乳动物中，在体外使用细胞系和初级免疫细胞进行评估。此外，CHIT 1的调节进行了analysed.ResultsHere，我们表明，CHIT 1转换成可扩散的低聚物，可以通过TLR1/TLR2共受体/受体异源二聚体，脂多糖结合蛋白（LBP）和CD14促进的过程中感测到的惰性聚合几丁质。此外，我们观察到Chit 1是通过b-葡聚糖受体Dectin-1诱导的，当永生化的人巨噬细胞直接接触真菌病原体白色念珠菌时，而所定义的真菌分泌的乙酰化蛋白酶，Sap 2和Sap 6，来自C. albicans were able to degrade CHIT 1 in vitro. DiscussionOur study showed the existence of a inducible system of MAMP generation in human host that enables contact-independent immune activation by diffusible MAMP ligands with a striking similarity to the plant kingdom.此外，这项研究突出了CHIT1作为TLR2介导的炎症过程的潜在治疗靶点，这些炎症过程由寡聚几丁质引起。
IntroductionChitin 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.MethodsThe 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.ResultsHere, 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 thatChit1is induced via the b-glucan receptor Dectin-1 upon direct contact of immortalized human macrophages to the fungal pathogenCandida albicans, whereas the defined fungal secreted aspartyl proteases, Sap2 and Sap6, fromC. albicanswere able to degrade CHIT1in vitro.DiscussionOur 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.
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DOI：
10.1038/jid.2010.351
发表时间：
2011-03
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
32.4
作者：
Eckert, Jana K.;Kim, Young J.;Schumann, Ralf R.
通讯作者：
Schumann, Ralf R.
影响因子：
7
作者：
Lee, Chun Geun;Da Silva, Carla A.;Lee, Jae-Young;Hartl, Dominik;Elias, Jack A.
通讯作者：
Elias, Jack A.
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
32.4
作者：
Kang, Jin Young;Nan, Xuehua;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh