Trace levels of peptidoglycan in serum underlie the NOD-dependent cytokine response to endoplasmic reticulum stress

Molinaro, Raphael; Mukherjee, Tapas; Flick, Robert; Philpott, Dana J.; Girardin, Stephen E.

doi:10.1074/jbc.ra119.007997

Cited by 42 publications

(39 citation statements)

References 41 publications

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“…[23][24][25] By comparing the expression of TLR-induced genes at baseline, we discovered a reduced TLR2-activation (PAM3CSK4) gene signature in Trim21 À/À BMDMs (Fig. Tonic TLR signaling occurs as the result of bacterial contaminants in serum, as previously reported.…”

Section: Expression Of Trim21 In Macrophages and Dendritic Cellssupporting

confidence: 66%

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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TRIM21 is an interferon-stimulated E3 ligase that controls the activity of pattern-recognition signaling via ubiquitination of interferon regulatory factors and DDX41. Previous studies on the role of TRIM21 in innate immune responses have yielded contradictory results, suggesting that the role of TRIM21 is cell specific. Here, we report that bone-marrow-derived macrophages (BMDMs) generated from Trim21 À/À mice have reduced expression of mature macrophage markers. Reflecting their reduced differentiation in response to macrophage colony-stimulating factor (M-CSF), Trim21 À/À BMDMs had decreased expression of M-CSF signature genes. Although Trim21 À/À BMDMs responded normally to Toll-like receptor 9 (TLR9) activation, they produced lower levels of pro-inflammatory cytokines in response to the TLR2 agonist PAM3CSK4. In line with this, the response to infection with the Bacillus Calmette-Gu erin strain of Mycobacterium bovis was also diminished in Trim21 À/À BMDMs. Our results indicate that TRIM21 controls responses to TLR2 agonists.

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Section: Expression Of Trim21 In Macrophages and Dendritic Cellssupporting

confidence: 66%

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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“…NOD1 and NOD2 may also be activated in response to calcium influx, as thapsigargin induces ER stress through inhibition of the sarco endoplasmic reticulum Ca 2+ ATPase (SERCA) that results in calcium influx. In intestinal epithelial cell lines and murine derived intestinal organoids, thapsigargin treatment results in a NOD1, NOD2, and RIP2 dependent transcriptional increase in pro-inflammatory cytokines CXCL1 and IL-8, and the chemokine CCL20 [ 34 ]. Similarly, NOD1 and NOD2-dependent cytokine/chemokine induction was also induced in response to the calcium ionophore A23187, but not other ER stress inducers like TM or the SubAB toxin of Shiga toxigenic Escherichia coli in intestinal epithelial cells [ 34 ].…”

Section: Nod1 and Nod2 As Mediators Of Cellular Metabolic Stressmentioning

confidence: 99%

“…It is unclear, however, whether NOD1 and NOD2 are activated directly by calcium signaling or through calcium-dependent influx of trace peptidoglycan fragments present in serum [ 34 ]. Using high pressure liquid chromatography coupled mass spectrometry, it was revealed that trace amounts of peptidoglycan fragments are detectable in animal serum.…”

Section: Nod1 and Nod2 As Mediators Of Cellular Metabolic Stressmentioning

confidence: 99%

Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2

Zangara

Johnston

Johnson

et al. 2021

IJMS

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In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.

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“…NOD2 contains a predicted TRAF2-binding motif in its nucleotide-binding oligomerization domain (Schneider et al, 2012) and could therefore function as the link between ER stress and inflammatory signaling. A recent study confirmed that thapsigargin induces NOD-dependent pro-inflammatory signaling, although this was due to the compound’s inhibition of the sarcoplasmic or endoplasmic reticulum calcium ATPase family (SERCA), which is responsible for Ca 2+ movement into the ER and cellular Ca 2+ regulation (Molinaro et al, 2019). Thapsigargin-induced depletion of Ca 2+ within the ER led to a rise in intracellular Ca 2+ levels and enhanced both Ca 2+ internalization and endocytosis.…”

Section: Activation Of the Nod Pathwaymentioning

confidence: 99%

NOD Signaling and Cell Death

Heim

Stafford

Nachbur

2019

Front. Cell Dev. Biol.

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Innate immune signaling and programmed cell death are intimately linked, and many signaling pathways can regulate and induce both, transcription of inflammatory mediators or autonomous cell death. The best-characterized examples for these dual outcomes are members of the TNF superfamily, the inflammasome receptors, and the toll-like receptors. Signaling via the intracellular peptidoglycan receptors NOD1 and NOD2, however, does not appear to follow this trend, despite involving signaling proteins, or proteins with domains that are linked to programmed cell death, such as RIP kinases, inhibitors of apoptosis (IAP) proteins or the CARD domains on NOD1/2. To better understand the connections between NOD signaling and cell death induction, we here review the latest findings on the molecular regulation of signaling downstream of the NOD receptors and explore the links between this immune signaling pathway and the regulation of cell death.

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Trace levels of peptidoglycan in serum underlie the NOD-dependent cytokine response to endoplasmic reticulum stress

Cited by 42 publications

References 41 publications

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2

NOD Signaling and Cell Death

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