Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele

Hedl, Matija; Lahiri, Amit; Ning, Kaida; Cho, Judy H.; Abraham, Clara

doi:10.1016/j.immuni.2014.04.011

Cited by 57 publications

(84 citation statements)

References 45 publications

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“…22 In the HapMap database, ICOSLG rs7282490 shows strong linkage disequilibrium with the ICOSLG rs2838519 genetic polymorphism, which is associated with both PBC and CD susceptibility in the present study. These reports indicate that loss of function in ICOSLG rs7282490 might be associated with a shared clinical feature, granuloma formation, in both diseases.…”

Section: Discussionsupporting

confidence: 54%

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

et al. 2015

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We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

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Section: Discussionsupporting

confidence: 54%

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

et al. 2015

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“…Intestinal lamina propria cell isolation. Intestinal lamina propria cells were isolated from colonic resection specimens from uninvolved intestine in 7 non-IBD patients undergoing surgery for diverticular disease or colon cancer (9). mRNA expression analysis.…”

Section: Author Contributionsmentioning

confidence: 99%

“…In intestinal tissues, multiple other PRRs are activated, the outcomes of which might in turn be modulated by additional IBD risk loci. Polymorphisms resulting in both decreased (e.g., NOD2, IL18RAP, ICOSL, ATG16L1, CARD9) and increased (e.g., MAP3K8, TNFSF15, IRF5) PRR-mediated signaling and downstream outcomes can be associated with intestinal inflammation (2)(3)(4)(5)(6)(7)(8)(9)(10)(11), thereby highlighting the critical role of balance in regulation of PRR-initiated outcomes in intestinal tissues. Despite the success in identification of IBD-associated loci (12), altered functions for most of the IBD loci are unknown.…”

Section: Introductionmentioning

confidence: 99%

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

Yan¹,

Hedl²,

Abraham³

2017

Journal of Clinical Investigation

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“…PKCs consist of conventional PKCs (eg, PKCα and β) and atypical PKCs (eg, PKCζ), and we previously found that both PKC types contribute to NOD2-initiated cytokine secretion. 31 Upon successful knockdown of PKCα, β and ζ (figure 4F), we found that each kinase was required for TPL2 phosphorylation on Thr290 (figure 4G). Knockdown of MAPKs, which have not been reported to affect upstream TPL2 signalling, did not affect TPL2 phosphorylation (data not shown).…”

Section: Prr Stimulation Regulates Tpl2 Expressionmentioning

confidence: 97%

ATPL2 (MAP3K8)disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion

Hedl

Abraham

2015

Gut

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Objective IBD is characterised by dysregulated intestinal immune homeostasis and cytokine secretion. In the intestine, properly regulating pattern recognition receptor (PRR)-mediated signalling and cytokines is crucial given the ongoing host–microbial interactions. TPL2 (MAP3K8, COT) contributes to PRR-initiated pathways, yet the mechanisms for TPL2 signalling contributions in primary human myeloid cells are incompletely understood and its role in intestinal myeloid cells is poorly defined. Furthermore, functional consequences for the IBD-risk locus rs1042058 in TPL2 are unknown. Methods We analysed protein, cytokine and RNA expression, and signalling in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR and flow cytometry. Results PRR-induced cytokine secretion was increased in MDMs from rs1042058 TPL2 GG risk individuals. TPL2 activation by the Crohn's disease-associated PRR nucleotide-oligomerisation domain (NOD)2 required PKC, and IKKβ, IKKα and IKKγ signalling. TPL2, in turn, significantly enhanced NOD2-induced ERK, JNK and NFκB signalling. We found that another major mechanism for the TPL2 contribution to NOD2 signalling was through ERK-dependent and JNK-dependent caspase-1 and caspase-8 activation, which in turn, led to early autocrine interleukin (IL)-1β and IL-18 secretion and amplification of long-term cytokines. Importantly, Salmonella typhimurium-induced cytokines from human intestinal myeloid-derived cells required TPL2 as well as autocrine IL-1β and IL-18. Finally, rs1042058 GG risk carrier MDMs from healthy individuals and patients with Crohn's disease had increased TPL2 expression and NOD2-initiated TPL2 phosphorylation, ERK, JNK and NFκB activation, and early autocrine IL-1β and IL-18 secretion. Conclusions Taken together, the rs1042058 GG IBD-risk polymorphism in TPL2 results in a gain-of-function by increasing TPL2 expression and signalling, thereby amplifying PRR-initiated outcomes.

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Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele

Cited by 57 publications

References 45 publications

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

ATPL2 (MAP3K8)disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion

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