LYSMD3: A mammalian pattern recognition receptor for chitin

He, Xin; Howard, Brad; Liu, Yang; Neumann, Aaron K.; Li, Liwu; Menon, Nidhi; Roach, Tiffany G.; Kale, Shiv D.; Samuels, David C.; Li, Hongyan; Kite, Trenton; Kita, Hirohito; Hu, Tony; Luo, Mengyao; Jones, Coleen; Okaa, Uju Joy; Squillace, Diane L.; Klein, Bruce S.; Lawrence, Christopher B.

doi:10.1016/j.celrep.2021.109392

Cited by 28 publications

(19 citation statements)

References 57 publications

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“…activation of multiple different human innate immune cell types and stimulation of adaptive immune responses. Compared to earlier results, chitin oligomers thus not only possess a strong capacity to fully signal danger to epithelial 11 and myeloid innate cell types (e.g. macrophages, PMNs) 10, 15 but also to lymphoid innate immune cells such as NK cells.…”

Section: Resultscontrasting

confidence: 70%

“…Additionally, we identified the innate immune receptor Toll-like receptor (TLR2) as a primary fungal chitin sensor on human and murine myeloid cells {Fuchs, 2018 #9694} and the host chitinase CHIT1 as an enzyme involved in oligomer generation 10 . Illustrating the validity of using pure chitin oligomers, He and colleagues have also shown that chitin oligomers can be recognized by the Lysin motif (LysM)-domain containing receptor LYSMD3 on the surface of human airway epithelial cells and elicit production of inflammatory cytokines 11 . However, so far the effects of oligomeric chitin on lymphoid innate (NK cells) and adaptive (B and T lymphocytes) immune cells have not been addressed.…”

Section: Introductionmentioning

confidence: 99%

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Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation

Gloria¹,

Fuchs²,

Chang³

et al. 2022

Preprint

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Background: Chitin is a highly abundant N-acetyl-glucosamine (GlcNAc) polysaccharide which has been linked to immune responses in the context of fungal infections and allergic asthma, especially T helper 2 (Th2) immune responses. Unfortunately, due to the frequent use of crude chitin preparations of unknown purity and degree of polymerization there is still great uncertainty how chitin activates different parts of the human immune system. Objective: We recently identified chitin oligomers of six GlcNAc units as the smallest immunologically active chitin motif and the innate immune receptor TLR2 as primary chitin sensor on human and murine myeloid cells, but the response of lymphoid cells to oligomeric chitin has not been investigated and was addressed here. Methods: Flow cytometric analysis of primary human immune cells upon stimulation with oligomeric chitin. Results: Here we report that chitin oligomers also activate immune responses by both primary lymphoid innate and adaptive immune cells: Notably, chitin oligomers activated Natural Killer (NK) cells and B lymphocytes. Moreover, the maturation of dendritic cells enabled CD8 T cell recall responses. Conclusions: Our results suggest that chitin oligomers not only trigger immediate innate responses in limited range of myeloid cells but exert critical activities across the entire human immune system.

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Section: Resultscontrasting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation

Gloria¹,

Fuchs²,

Chang³

et al. 2022

Preprint

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Section: Introductionmentioning

confidence: 99%

“…In these organisms, chitin is a model microbe-associated molecular pattern (MAMP), as evidenced by the existence of chitin-mediated activation of immune responses through pattern recognition receptors (PRRs) [5, 6]. Chitin is sensed through the receptor CERK1 and its co-receptor CEBiP in plants [7] [8] and in humans by Toll-like receptor (TLR) 2 in immune cells [9] and by FIBCD1 or LYSMD3 on epithelial cells [10, 11]. However, during initial exposure, the mammalian host encounters chitin in a highly polymeric and insoluble form of exoskeleton particles of house dust mites or the cell wall of pathogenic fungi, have a form that has been considered immunologically inert [4].…”

Section: Introductionmentioning

confidence: 99%

Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing

Chang

Gloria

Hellmann

et al. 2022

Preprint

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Chitin is a highly abundant polysaccharide in nature and linked to immune recognition of fungal infections and asthma in humans. Ubiquitous in fungi and insects, chitin is absent in mammals and plants and, thus, represents a microbe-associated molecular pattern (MAMP). However, the 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. Here, we show that the secreted chitinolytic host enzyme, 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 Chit1 is induced via the beta-glucan receptor Dectin-1 upon direct contact of immortalized human macrophages to the fungal pathogen Candida albicans, whereas the defined fungal secreted aspartyl proteases, Sap2 and Sap6, from C. albicans were able to degrade CHIT1 in vitro. 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 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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“…Mannans are also recognized by host cells [28] and may also provide a barrier to limit access of fungicidal molecules to the plasma membrane [31]. The full role of chitin in recognition of C. albicans at the host epithelia is unclear and the subject of ongoing research [32], but it has been shown that purified C. albicans chitin upregulates production of the antiinflammatory cytokine IL-10 in macrophages [33]. The rearrangement of the cell wall due to stress and other stimuli (i.e., treatment with a cell-surface damaging antifungal drug) can result in changes in the distribution of all 3 components at the cell surface and can cause unmasking of β-1,3 glucan [34].…”

Section: Introductionmentioning

confidence: 99%

A Novel Role for Histatin 5 in Combination with Zinc to Promote Commensalism in C. albicans Survivor Cells

2021

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Candida albicans is maintained as a commensal by immune mechanisms at the oral epithelia. Oral antifungal peptide Histatin 5 (Hst 5) may function in innate immunity, but the specific role Hst 5 plays in C. albicans commensalism is unclear. Since Zn-binding potentiates the candidacidal activity of Hst 5, we hypothesized that Hst 5+Zn would elicit a unique fungal stress response to shape interactions between C. albicans and oral epithelial cells (OECs). We found that Hst 5+Zn but not Hst 5 alone resulted in the activation of cell wall integrity (CWI) signaling, and deletion mutants were then used to determine that CWI-mediated chitin synthesis was protective against killing. Using flow cytometry, we confirmed that Hst 5+Zn-treated cells had significantly elevated levels of cell-wall chitin, mannan and β-1,3 glucan compared to Hst 5-treated cells. We then tested the activation of host signaling components involved in C. albicans cell-wall recognition. The immunoblot assay of C. albicans-exposed oral epithelial cells showed increased activation of EphA2 and NF-κB but not EGFR. Interestingly, C. albicans treated with Hst 5+Zn induced the global suppression of pro-inflammatory cytokine release from OECs, but an increase in negative regulator IL-10. Hst 5+Zn-treated cells were more adherent but ultimately less invasive to OECs than control cells, thus indicating lowered virulence. Therefore, Hst 5+Zn-treated C. albicans cells are discerned by epithelial monolayers, but are less virulent and promote anti-inflammatory signaling, suggesting that Hst 5+Zn in combination could play a role in regulating commensalism of oral C. albicans through cell wall reorganization.

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LYSMD3: A mammalian pattern recognition receptor for chitin

Cited by 28 publications

References 57 publications

Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation

Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation

Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing

A Novel Role for Histatin 5 in Combination with Zinc to Promote Commensalism in C. albicans Survivor Cells

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