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Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis.

ABSTRACT: Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO (IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with caerulein, NEMO^ΔCol1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with reduced latency period. Transcriptomic profiling shows that NEMO^ΔCol1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSC^ΔNEMO cells produce high levels of CCL24 ex vivo which contributes to eosinophil recruitment, as neutralization with a CCL24 antibody abolishes the transwell migration of eosinophils. Our findings uncover an unexpected immunomodulatory role specifically of NF-κB in PSCs during pancreatitis.

SUBMITTER: Chan LK

PROVIDER: S-EPMC9142538 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis.

Chan Lap Kwan LK Tsesmelis Miltiadis M Gerstenlauer Melanie M Leithäuser Frank F Kleger Alexander A Frick Lukas Daniel LD Maier Harald Jacob HJ Wirth Thomas T

Communications biology 20220527 1

Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO (IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged ...[more]

PMID: 35624133

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Project description:BackgroundAirway hyperresponsiveness (AHR) is characterized by excessive contraction of airway smooth muscle, leading to airflow limitation, increasing perioperative airway spasm and even triggering the defense of silent lungs, which can lead to delayed surgery. Stellate ganglion blockade (SGB) has gained attention for its immunomodulatory and anti-inflammatory effects; however, its impact on AHR and the underlying mechanisms remain unexplored. This study aims to evaluate whether SGB reduces AHR and if this effect is related to inflammation.MethodsThe experimental groups included Control, OVA (ovalbumin-induced AHR), OVA + SGB2, OVA + SGB4, OVA + SGB5, OVA + SGB6, OVA + SGB8, OVA + 4PBA, Tm, and Tm + SGB6. Mice underwent varying numbers of SGB interventions over 17 days. On day 18, lung function tests were performed, followed by ELISA of IL-4, IL-5, and IL-13 levels in alveolar lavage fluid from the right lung, and finally, tissue from the right lung was extracted for transcriptome analysis, and tissue from the left lung (without lavage fluid) was stained with HE staining to assess histopathological changes.ResultsCompared to the Control group, the OVA group exhibited increased overall respiratory resistance (Rrs), overall respiratory elasticity (Ers), central airway resistance (Rn), peripheral tissue elasticity (H), and tissue damage (G), alongside decreased overall respiratory compliance (Crs) (P < 0.05). SGB significantly improved lung function parameters, with the OVA + SGB6 group showing the most pronounced improvement (P < 0.05). The Tm group displayed elevated Rrs compared to Control (P < 0.05), while the OVA + 4PBA group demonstrated significant improvement in Rrs (P < 0.05). The Tm + SGB6 group also showed significant improvement in Rrs compared to the Tm group (P < 0.05). The expression of IRE1β-IKK/NF-κB genes was upregulated in the OVA group and downregulated in the OVA + SGB6 group. Furthermore, ER stress inhibitors reduced the expression of these key genes in OVA-induced AHR. Notably, the expression of ER stress-related genes was elevated in the OVA group, with a significant decrease in Agr2 (a promoter of ER stress IRE1β) observed in the OVA + SGB6 group compared to the OVA group (114 vs. 16).ConclusionSGB effectively reduced AHR while down-regulating the expression of key genes in the IKK/NF-κB/IL-4/IL-5/IL-13 signaling pathway, which may be related to IRE1β-mediated endoplasmic reticulum stress. However, further studies are needed to confirm the exact mechanism.

Dataset Information

Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis.

Publications

Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis.

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