Dataset Information

The immune receptor TLR2 directly binds and signals immune activation to oligomeric chitin

ABSTRACT: Chitin is the second most abundant polysaccharide in nature and a biomolecule intimately linked to fungal infection and allergic asthma, conditions that affect millions of patients worldwide. Chitin is known to stimulate multiple mammalian immune cells, but the precise molecular sensing mechanism has not been elucidated, hampering strategies to specifically target chitin-mediated pathologies. Using defined chitin oligomers we here identify six chitin subunits as the smallest immunologically active chitin motif and the innate immune receptor TLR2 as the molecular chitin sensor on human and murine immune cells, in vitro and in vivo. Chitin oligomers directly bound TLR2 with nanomolar affinity and elicited overlapping yet distinct signaling outcomes compared to canonical TLR2 ligands. Conversely, chitin oligomers composed of five chitin subunits acted as antagonists of chitin-TLR2 immune activation, hinting to an anti-inflammatory loop already known from plants, to also operate in humans. Of note, small chitin oligomers and biological-based blocking of the TLR2-chitin interaction effectively prevented chitin-mediated inflammation not only in vitro but also in vivo. Collectively, our study elucidates the molecular basis of how chitin is sensed by mammalian immune cells, which has broad impact for chitin-associated inflammatory pathologies. From a translational perspective, our findings further suggests that differently sized chitin oligomers could be developed into novel vaccine adjuvants or immuno-modulatory antagonists for the prevention or treatment of chitin-driven diseases in humans.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Macrophage

SUBMITTER: Nicolas Nalpas

LAB HEAD: Alexander N.R. Weber

PROVIDER: PXD007542 | Pride | 2019-11-12

REPOSITORIES: Pride

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			Action	DRS
	20170528_CT_R2_THP1_Dimeth_LMH_Chitin0_Chitin30_Pam230_7_9mg_TiO2_1mg_HpH_01.raw	Raw
	20170528_CT_R2_THP1_Dimeth_LMH_Chitin0_Chitin30_Pam230_7_9mg_TiO2_1mg_HpH_02.raw	Raw
	20170528_CT_R2_THP1_Dimeth_LMH_Chitin0_Chitin30_Pam230_7_9mg_TiO2_1mg_HpH_03.raw	Raw
	20170528_CT_R2_THP1_Dimeth_LMH_Chitin0_Chitin30_Pam230_7_9mg_TiO2_1mg_HpH_04.raw	Raw
	20170528_CT_R2_THP1_Dimeth_LMH_Chitin0_Chitin30_Pam230_7_9mg_TiO2_1mg_HpH_05.raw	Raw

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Publications

Putative link between Polo-like kinases (PLKs) and Toll-like receptor (TLR) signaling in transformed and primary human immune cells.

El Maadidi Souhayla S Weber Alexander N R ANR Motshwene Precious P Schüssler Jan Moritz JM Backes Daniel D Dickhöfer Sabine S Wang Hui H Liu Xiao X Garcia Magno Delmiro MD Taumer Christoph C Soufi Boumediene B Wolz Olaf-Oliver OO Klimosch Sascha N SN Franz-Wachtel Mirita M Macek Boris B Gay Nicholas J NJ

Scientific reports 20190911 1

Toll-like receptors (TLRs) are important sentinels of bacterial and viral infection and thus fulfil a critical sensory role in innate immunity. Polo-like kinases (PLKs), a five membered family of Ser/Thr protein kinases, have long been studied for their role in mitosis and thus represent attractive therapeutic targets in cancer therapy. Recently, PLKs were implicated in TLR signaling in mice but the role of PLKs in TLR signaling in untransformed primary immune cells has not been addressed, even ...[more]

PMID: 31511529

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Project description:A LysM Receptor-like Kinase Mediates Chitin Perception and Fungal Resistance in Arabidopsis; Jinrong Wan,1 Xuecheng Zhang,1 David Neece,2 Katrina M. Ramonell,3 Steve Clough,2,4 Sung-yong Kim,1 Minviluz Stacey,1 and Gary Stacey1*; 1Division of Plant Sciences, National Center for Soybean Biotechnology, C.S. Bond Life Sciences Center, University of Missouri-Columbia, Columbia, MO 65211, USA; 2Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; 3Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA; 4US Department of Agriculture, Soybean/Maize Germplasm, Pathology and Genetics Research, Urbana, IL 61801, USA; *To whom correspondence should be addressed. E-mail: staceyg@missouri.edu; Abstract: Chitin, a polymer of N-acetyl-D-glucosamine, is found in fungal cell walls, but not in plants. Plant cells are capable of perceiving chitin fragments (chitooligosaccharides) to trigger various defense responses. We identified a LysM receptor-like protein (AtLysM RLK1) that is required for the perception of chitooligosaccharides in Arabidopsis. Mutation of this gene blocked the induction of almost all chitooligosaccharide-responsive genes (CRGs) and led to more susceptibility to fungal pathogens, but not to a bacterial pathogen. In addition, exogenously applied chitooligosaccharides enhanced resistance against both fungal and bacterial pathogens in the wild-type plants, but not in the mutant. Together, our data strongly suggest AtLysM RLK1 is the chitin receptor or a key part of the receptor complex and chitin is a PAMP (pathogen-associated molecular pattern) in fungi recognized by the receptor leading to the induction of plant innate immunity against fungal pathogens. Since LysM RLKs were also recently shown to be critical for the perception of the rhizobial lipo-chitin Nod signals, our data suggest that LysM RLKs not just recognize friendly symbiotic rhizobia (via their lipo-chitin Nod signals), but also hostile fungal pathogens (via their cell wall chitin). These data suggest a possible evolutionary relationship between the perception mechanisms of Nod signals and chitin by plants. Experiment Overall Design: wild type Col-0 and chitin receptor mutants treated with or without chitooctaose