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Human buccal epithelium acquires microbial hyporesponsiveness at birth, a role for secretory leukocyte protease inhibitor
  1. Celia L Menckeberg1,
  2. Jeroen Hol1,2,3,
  3. Ytje Simons-Oosterhuis1,
  4. H (Rolien) C Raatgeep1,
  5. Lilian F de Ruiter1,2,
  6. Dicky J Lindenbergh-Kortleve1,
  7. Anita M Korteland-van Male1,
  8. Sahar El Aidy4,5,
  9. Pieter P E van Lierop1,
  10. Michiel Kleerebezem4,
  11. Michael Groeneweg6,
  12. Georg Kraal7,
  13. Beatrix E Elink-Schuurman2,
  14. Johan C de Jongste2,
  15. Edward E S Nieuwenhuis1,8,
  16. Janneke N Samsom1
  1. 1Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus MC, Rotterdam, The Netherlands
  2. 2Department of Pulmonary Diseases, Sophia Children's Hospital, Rotterdam, The Netherlands
  3. 3Department of Pediatrics, University Hospital Ghent, Ghent, Belgium
  4. 4Laboratory of Microbiology and Host Microbe Interactomics Group, Wageningen University, Wageningen, The Netherlands
  5. 5Department of Industrial Biotechnology, GEBRI, Sadat City University, Sadat City, Egypt
  6. 6Department of Pediatrics, Maasstad Hospital, Rotterdam, The Netherlands
  7. 7Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
  8. 8Wilhelmina Children's Hospital, Utrecht, The Netherlands
  1. Correspondence to Dr Janneke N Samsom PhD, Erasmus University Medical Center, Laboratory of Pediatric Gastroenterology, Room EE1567A, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; j.samsom{at} Dr Edward ES Nieuwenhuis MD, PhD, UMC Utrecht Room KA 03.023.3 P.O. Box 85090, 3508 AB Utrecht, The Netherlands;


Objective Repetitive interaction with microbial stimuli renders epithelial cells (ECs) hyporesponsive to microbial stimulation. Previously, we have reported that buccal ECs from a subset of paediatric patients with Crohn's disease are not hyporesponsive and spontaneously released chemokines. We now aimed to identify kinetics and mechanisms of acquisition of hyporesponsiveness to microbial stimulation using primary human buccal epithelium.

Design Buccal ECs collected directly after birth and in later stages of life were investigated. Chemokine release and regulatory signalling pathways were studied using primary buccal ECs and the buccal EC line TR146. Findings were extended to the intestinal mucosa using murine model systems.

Results Directly after birth, primary human buccal ECs spontaneously produced the chemokine CXCL-8 and were responsive to microbial stimuli. Within the first weeks of life, these ECs attained hyporesponsiveness, associated with inactivation of the NF-κB pathway and upregulation of the novel NF-κB inhibitor SLPI but no other known NF-κB inhibitors. SLPI protein was abundant in the cytoplasm and the nucleus of hyporesponsive buccal ECs. Knock-down of SLPI in TR146-buccal ECs induced loss of hyporesponsiveness with increased NF-κB activation and subsequent chemokine release. This regulatory mechanism extended to the intestine, as colonisation of germfree mice elicited SLPI expression in small intestine and colon. Moreover, SLPI-deficient mice had increased chemokine expression in small intestinal and colonic ECs.

Conclusions We identify SLPI as a new player in acquisition of microbial hyporesponsiveness by buccal and intestinal epithelium in the first weeks after microbial colonisation.

  • Epithelial Cells
  • Gut Immunology
  • IBD Basic Research
  • Bacterial Interactions

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