The non-canonical NF-κB pathway in immunity and inflammation

Sun, Shao Cong

doi:10.1038/nri.2017.52

Cited by 1,355 publications

(1,252 citation statements)

References 177 publications

(286 reference statements)

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“…Calcium also plays a role in canonical NF-κB activation in response to genotoxic stress [97], but the mechanism underlying this response remains unclear, and it is not known whether Ca 2+ regulates this pathway in lymphocytes. However, a distinct NF-κB signaling mechanism termed the “non-canonical pathway” also controls key steps of lymphocyte development, fate and function [98]. The non-canonical pathway is not activated by BCR or TCR engagement but rather by a subset of TNF receptor family members expressed on the surface of B and / or T cells including BAFFR, LTβR, CD40, CD30, Ox40, TWEAK and RANK [98].…”

Section: Multiple Ca2+ Regulated Checkpoints Control Nf-κb Activitmentioning

confidence: 99%

STIM- and Orai-mediated calcium entry controls NF-κB activity and function in lymphocytes

2018

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The central role of Ca signaling in the development of functional immunity and tolerance is well established. These signals are initiated by antigen binding to cognate receptors on lymphocytes that trigger store operated Ca entry (SOCE). The underlying mechanism of SOCE in lymphocytes involves TCR and BCR mediated activation of Stromal Interaction Molecule 1 and 2 (STIM1/2) molecules embedded in the ER membrane leading to their activation of Orai channels in the plasma membrane. STIM/Orai dependent Ca signals guide key antigen induced lymphocyte development and function principally through direct regulation of Ca dependent transcription factors. The role of Ca signaling in NFAT activation and signaling is well known and has been studied extensively, but a wide appreciation and mechanistic understanding of how Ca signals also shape the activation and specificity of NF-κB dependent gene expression has lagged. Here we discuss and interpret what is known about Ca dependent mechanisms of NF-kB activation, including what is known and the gaps in our understanding of how these signals control lymphocyte development and function.

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Section: Multiple Ca2+ Regulated Checkpoints Control Nf-κb Activitmentioning

confidence: 99%

STIM- and Orai-mediated calcium entry controls NF-κB activity and function in lymphocytes

2018

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“…Mst1/2-deficient CD8α + DCs had reduced expression of NF-κB2 and RelB, which are involved in the non-canonical NF-κB pathway 17 (Fig. 4b, f and Extended Data Fig.…”

mentioning

confidence: 94%

“…10e). Further, Traf3, a key regulator of non-canonical NF-κB/NIK signaling 17 , interacted with Mst1 in CD8α + DCs (Extended Data Fig. 10f), although Traf3 expression was unaltered by Mst1/2 deficiency (Extended Data Fig.…”

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confidence: 99%

Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells

Wen

Wang

et al. 2018

Nature

166

145

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Dendritic cells (DCs) orchestrate the crosstalk between innate and adaptive immunity. CD8α+ DCs present antigens to CD8+ T cells and elicit cytotoxic T-cell responses to viruses, bacteria and tumors1. Although lineage-specific transcriptional regulators of CD8α+ DC development have been identified2, the molecular pathways that selectively orchestrate CD8α+ DC function remain elusive. Moreover, metabolic reprogramming is important for DC development and activation3,4, but metabolic dependence and regulation of DC subsets are unknown. Here, we describe a data-driven systems biology algorithm (NetBID) and an unexpected role of Hippo pathway kinases, Mst1 and Mst2 (Mst1/2), in selectively programming CD8α+ DC function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ DCs relative to CD8α− DCs. DC-specific deletion of Mst1/2, but not Lats1/2 or Yap/Taz that mediate canonical Hippo signaling, disrupts homeostasis and function of CD8+ T cells and anti-tumor immunity. Mst1/2-deficient CD8α+ DCs are impaired in presenting extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α− DCs lacking Mst1/2 have largely normal function. Mechanistically, compared with CD8α− DCs, CD8α+ DCs show much stronger oxidative metabolism and critically depend upon Mst1/2 signaling to maintain bioenergetic activities and mitochondrial dynamics for functional capacities. Further, CD8α+ DCs selectively express IL-12 that depends upon Mst1/2 and the crosstalk with non-canonical NF-κB signaling. Our findings identify Mst1/2 as selective drivers of CD8α+ DC function by integrating metabolic activity and cytokine signaling, and highlight that the interplay between immune signaling and metabolic reprogramming underlies the unique function of DC subsets.

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“…The NF-κB and Stat3 transcriptional factors are critical regulators in cell signalling and play an important role in inflammation- promoted cancers [34][35][36][37]. NF-κB and Stat3 activated by inflammation regulate transcription and expression of various genes, including genes involved in immune response, cell proliferation and apoptosis [38][39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells

Zhou

Xia

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic inflammation plays an important role in the initiation and progression of gastric cancer (GC). However, the role and relationship of activated macrophages with gastric mucous epithelium cells in initiating and maintaining the inflammatory process during gastric carcinogenesis remains unclear. Methods: The tumour associated macrophages (TAMs) density of gastric cancer was characterized by immunohistochemistry, and the relationship between macrophages and gastric epithelium cells was analysed using an in vitro culture system that imitates the inflammatory microenvironment. The production of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). MTT assays, Western blotting, qRT-PCR, and luciferase reporter assays were used to detect the effects of cell proliferation, as well as the NF-κB and STAT3 signalling pathways. Results: TAMs infiltrated with a high intensity in GC and were significantly correlated with histology grade (P = 0.012), metastasis (P = 0.001), TNM stage (P = 0.002), and poor prognosis in patients (PFS, P = 0.005; OS, P = 0.028). In addition, IL-6 and IL-8 were elevated in the serum of GC patients and significantly promoted the growth of GC. The exposure of BGC823 gastric cancer cells to a conditioned medium from LPS-treated D-THP-1 cells significantly induced the production of TNF-α, IL-6, IL-1β and IL-8 (P< 0.01). LPS and LPS-treated D-THP-1-conditioned media promoted gastric cancer cell proliferation and triggered the significant activation of NF-κB and STAT3 with a concomitant degradation of IκBα and an increase in JAK2 phosphorylation (P < 0.05). Moreover, gastric cancer cells markedly expressed cell membrane LPS receptors, such as TLR1, TLR4, TLR6, CD14 and MD2. Conclusions: TAMs are closely associated with the growth of GC and prognosis in GC patients. GC cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-κB and STAT3 signalling pathways, thereby promoting tumour progression.

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The non-canonical NF-κB pathway in immunity and inflammation

Cited by 1,355 publications

References 177 publications

STIM- and Orai-mediated calcium entry controls NF-κB activity and function in lymphocytes

STIM- and Orai-mediated calcium entry controls NF-κB activity and function in lymphocytes

Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells

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