Intestinal non-canonical NFκB signaling shapes the local and systemic immune response

Ramakrishnan, S; Zhang, Huabing; Ma, Xiaoya; Jung, Inkyung; Schwartz, Andrew J.; Triner, Daniel; Devenport, Samantha; Das, Nupur K.; Xue, Xiang; Zeng, Melody Y.; Hu, Yinling; Mortensen, Richard M.; Greenson, Joel K.; Cascalho, Marília; Wobus, Christiane E.; Colacino, Justin A.; Núñez, Gabriel; Rui, Liangyou; Shah, Yatrik M.

doi:10.1038/s41467-019-08581-8

Cited by 74 publications

(61 citation statements)

References 70 publications

(95 reference statements)

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“…noncanonical NF-kB signaling in assisting M-cell development, we used lentiviruses to target NF-kappa-B-inducing kinase (NIK; encoded by MAP3K14) in human enteroids. Consistent with a recent report of NIK participation in intestinal lymphoid follicle formation, 26 genetic depletion of MAP3K14 led to reduced M-cell numbers by staining ( Figure 3B), suggesting that LT-NIK-RelB signaling is critical to efficient M-cell differentiation.…”

Section: Resultssupporting

confidence: 92%

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

et al. 2020

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Human and mouse ileum tissues Intestinal enteroid culture Functional M cells Enteric viruses RANKL RA, LT WRN See editorial on page 34. BACKGROUND & AIMS: Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer's patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids. METHODS: We analyzed transcriptome data from mouse Peyer's patches to identify cell populations in close proximity to M cells. We used the human enteroid system to determine which cytokines were required to induce M-cell differentiation. We performed transcriptome, immunofluorescence, scanning electron microscope, and transcytosis experiments to validate the development of phenotypic and functional human M cells. RESULTS: A combination of retinoic acid and lymphotoxin induced differentiation of glycoprotein 2-positive human M cells, which lack apical microvilli structure. Upregulated expression of innate immune-related genes within M cells correlated with a lack of viral antigens after rotavirus infection. Human M cells, developed in the enteroid system, internalized and transported enteric viruses, such as rotavirus and reovirus, across the intestinal epithelium barrier in the enteroids. CONCLUSIONS: We identified signaling pathways required for differentiation of intestinal M cells, and used this information to create a robust culture method to develop human M cells with capacity for internalization and transport of viruses. Studies of this model might increase our understanding of antigen presentation and the systemic entry of enteric pathogens in the human intestine.

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Section: Resultssupporting

confidence: 92%

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

et al. 2020

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“…NF-κB is a pivotal regulator of both innate and adaptive immunity within the TIME. [30][31][32] Thus, we further investigated whether the PI3K/Akt/ NF-κB signaling pathway was also involved in the immunomodulatory effect induced by low-dose chemotherapy. Consistent with this assumption, results from FACS data analysis revealed that the CDDP-induced or GEM-induced increases in PD-L1, MHC class I, HLA-A/B/C, and cytoplasmic HMGB-1 expression were abrogated in cells pretreated or co-incubated with BAY 11-7082 (NF-κB inhibitor), LY294002 (PI3K inhibitor), or MK2206 (Akt inhibitor), although to different extents (figure 1C-N).…”

Section: Resultsmentioning

confidence: 99%

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Wang

et al. 2020

J Immunother Cancer

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BackgroundThe survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.MethodsCell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.ResultsLow-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.ConclusionsWe first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

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“…The NF-κB signaling pathway is a key mediator of cytokine and chemokine transcription and plays a central role in the host response to infection by microbial pathogens. 29 NF-κB essential modulator binds to M1-linked Ub chains at the receptor signaling complex, enabling inhibitor of NF-κB kinase α and β (IKKα/β)-mediated phosphorylation and subsequent proteasomal degradation of NF-κB inhibitor α (IκBα) and nuclear translocation of gene-specific transcription factors. 30 S. typhimurium exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection that S. typhimurium induced NLRP12-mediated inhibition of NF-κB by targeting phosphorylation of IκBα in mice.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus johnsonii L531 ameliorates enteritis via elimination of damaged mitochondria and suppression of SQSTM1‐dependent mitophagy in a Salmonella infantis model of piglet diarrhea

Xia

et al. 2019

FASEB j.

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Newly weaned piglets challenged with Salmonella infantis were particularly susceptible, whereas oral preadministration of Lactobacillus johnsonii L531 alleviated enteritis and promoted intestinal secretory IgA production. Salmonella infantisinduced activation of NLRC4 and NLRP3 inflammasomes and (nuclear factor kappa B) NF-κB signaling in the small intestine was also inhibited by L. johnsonii L531 pretreatment, thus limiting inflammation. An IPEC-J2 cell model of S. infantis infection yielded similar results. Salmonella infantis infection also resulted in mitochondrial damage and impaired mitophagy in the ileum and IPEC-J2 cells, as demonstrated by immunofluorescence colocalization of mitochondria with microtubule-binding protein light chain 3 (LC3) and high expression of autophagy-related proteins PTEN-induced putative kinase 1 (PINK1), sequestosome 1 (SQSTM1/p62), optineurin (OPTN), and LC3 by Western blotting analysis. However, L. johnsonii L531 pretreatment reduced both the extent of mitochondrial damage and autophagyrelated protein expression. Our findings suggest that the amelioration of S. infantisassociated enteritis by L. johnsonii L531 is associated with regulation of NLRC4 and NLRP3 inflammasomes and NF-κB signaling pathway activation and suppression of mitochondrial damage. Amelioration of impaired mitophagy by L. johnsonii L531 could involve eliminating damaged mitochondria and regulating S. infantis-induced activation of the NF-κB-SQSTM1mitophagy signaling pathway in host cells to prevent the further mitochondrial damage and S. infantis dissemination. K E Y W O R D S autophagy, inflammasome, IPEC-J2, pig, probiotic 2822 |

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Intestinal non-canonical NFκB signaling shapes the local and systemic immune response

Cited by 74 publications

References 70 publications

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Lactobacillus johnsonii L531 ameliorates enteritis via elimination of damaged mitochondria and suppression of SQSTM1‐dependent mitophagy in a Salmonella infantis model of piglet diarrhea

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