Frontiers in Immunology (Sep 2024)

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn’s disease through IFNα pathway

  • Efstratios Gavriilidis,
  • Efstratios Gavriilidis,
  • Georgios Divolis,
  • Anastasia-Maria Natsi,
  • Nikolaos Kafalis,
  • Nikolaos Kafalis,
  • Dionysios Kogias,
  • Dionysios Kogias,
  • Christina Antoniadou,
  • Christina Antoniadou,
  • Evgenia Synolaki,
  • Evgenios Pavlos,
  • Marianna A. Koutsi,
  • Stylianos Didaskalou,
  • Evangelos Papadimitriou,
  • Evangelos Papadimitriou,
  • Victoria Tsironidou,
  • Ariana Gavriil,
  • Vasileios Papadopoulos,
  • Marios Agelopoulos,
  • Dimitrios Tsilingiris,
  • Maria Koffa,
  • Alexandra Giatromanolaki,
  • Georgios Kouklakis,
  • Georgios Kouklakis,
  • Konstantinos Ritis,
  • Konstantinos Ritis,
  • Panagiotis Skendros,
  • Panagiotis Skendros

DOI
https://doi.org/10.3389/fimmu.2024.1447608
Journal volume & issue
Vol. 15

Abstract

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IntroductionCrohn’s disease (CD) is characterized by chronic inflammation and intestinal fibrosis leading to lifelong complications. However, the disease pathogenesis remains elusive, and the therapeutic options are limited. Here, we investigated the interaction between neutrophils and intestinal fibroblasts in the development of CD immunofibrosis, a disease mechanism predisposing to inflammatory and fibrotic complications.MethodsPeripheral neutrophils, enriched neutrophil extracellular traps (eNETs), serum, primary intestinal fibroblasts (PIFs) and intestinal biopsies from CD, ulcerative colitis (UC) patients, and healthy individuals (HI), were studied. Transcriptome analysis of neutrophils, multi-cytokine profiling and cell-based functional assays at mRNA/protein level were performed.ResultsCompared to UC, PIFs from CD patients, independently to the presence of strictures, displayed a distinct pro-fibrotic phenotype characterized by negative Krüppellike Factor-2 (KLF2) and increased cellular communication network factor-2 (CCN2) expression leading to collagen production. In both UC and CD, PIFs-derived IL-8 acted as a culprit chemoattractant for neutrophils in the intestine, where CD neutrophils were accumulated close to fibrotic lesions. Functionally, only CD neutrophils via eNETs induced a CD-like phenotype in HI PIFs, suggesting their fibrotic plasticity. High IFNa in serum and IFΝ-responsive signature in peripheral neutrophils were observed in CD, distinguishing it from UC. Moreover, CD serum stimulated the release of fibrogenic eNETs from neutrophils in an IFNa-dependent manner, suggesting the priming role of IFNa in circulating neutrophils. Inhibition of eNETs or JAK signaling in neutrophils or PIFs prevented the neutrophil-mediated fibrotic effect on PIFs. Furthermore, both serum IFNa levels and mRNA levels of key IFN signaling components in neutrophils were wellcorrelated with CD severity.ConclusionsThis study reveals the important role of the IFNa/neutrophil/fibroblast axis in CD immunofibrosis, suggesting candidate biomarkers and putative therapeutic targets.

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