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            <i>TNFSF15</i>
            disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Hedl, Matija; Abraham, Clara

doi:10.1073/pnas.1404178111

Cited by 54 publications

(65 citation statements)

References 38 publications

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“…NOD2 stimulation activates the MAPK, NFκB, and PI3K pathways (11)(12)(13)(14)(15), and these pathways lead to cytokine secretion (15,16). We therefore asked if these pathways were modulated by MTMR3.…”

Section: Resultsmentioning

confidence: 99%

MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation

Lahiri

Hedl

Abraham

2015

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Host pattern recognition receptors (PRRs) are critical in regulating these interactions. Multiple genetic loci are associated with IBD, but altered functions for most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are unknown. We identified a previously undefined role for myotubularinrelated protein 3 (MTMR3) in amplifying PRR-induced cytokine secretion in human macrophages and defined MTMR3-initiated mechanisms contributing to this amplification. MTMR3 decreased PRR-induced phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, thereby increasing PRR-induced caspase-1 activation, autocrine IL-1β secretion, NFκB signaling, and, ultimately, overall cytokine secretion. This MTMR3-mediated regulation required the N-terminal pleckstrin homology-GRAM domain and Cys413 within the phosphatase domain of MTMR3. In MTMR3-deficient macrophages, reducing the enhanced autophagy or restoring NFκB signaling rescued PRRinduced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased PRR-induced PtdIns3P and autophagy and increased PRR-induced caspase-1 activation, signaling, and cytokine secretion. Thus, the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates PRR-induced outcomes, ultimately leading to enhanced PRR-induced cytokines.Crohn's disease | ulcerative colitis | NOD2 | genetics | Toll-like receptors I nflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune homeostasis and cytokine production (1). Given the key role for host-microbe interactions in the intestine, proper regulation of pattern recognition receptor (PRR) signaling and cytokine secretion is critical. Although a number of loci have now been associated with IBD (2), altered functions for the majority of these loci are unknown. Defining these functions is essential to our understanding of IBD pathophysiology and to our ability to ultimately target these implicated pathways.Polymorphisms in the MTMR3/HORMAD2/LIF/OSM region on chromosome 22 are associated with Crohn's disease and ulcerative colitis (2, 3), the two IBD subtypes. The specific gene(s) mediating the association and the functional consequences of the polymorphisms are not yet reported, although leukemia inhibitory factor (LIF) and Oncostatin M (OSM) have been proposed as candidates (2). Myotubularin-related protein 3 (MTMR3) is a member of the myotubularin family. Mutations in certain myotubularin members can lead to neuro-muscular diseases (4). Active myotubularin members possess phosphoinositide 3-protein tyrosine phosphatase activity; the active phosphatase domain located in the MTMR3 N-terminal region dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P 2 (4, 5). PtdIns3P is an important lipid mediator of membrane trafficking and signaling and participates in effector recruitment to autophagic membranes. Consistently, MTM...

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Section: Resultsmentioning

confidence: 99%

MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation

Lahiri

Hedl

Abraham

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…We first examined the signaling pathways regulated by INAVA upon NOD2 stimulation. Activation of MAPK and NF-κB pathways is critical for NOD2-induced cytokines (6,7,19,(24)(25)(26). Activation of the MAPKs ERK, p38, and JNK ( Figure 6A), and the NF-κB pathway ( Figure 6B) were impaired upon NOD2 stimulation of MDMs in which INAVA was knocked down.…”

Section: Mdms From Rs7554511 C Risk Carriers In Inava Demonstrate Decmentioning

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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“…27 37 In addition to caspase-1, we recently found that caspase-8 also contributes to NOD2-mediated IL-1β secretion. 39 We further found that caspase-8 was required for optimal early autocrine IL-18 secretion ( figure 6D). We therefore examined TPL2 regulation of these caspases.…”

Section: Prr Stimulation Regulates Tpl2 Expressionmentioning

confidence: 71%

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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A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Cited by 54 publications

References 38 publications

MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation

MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation

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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