Epithelial SLPI expression in severe inflammatory bowel disease relates to high IL-17 and neutrophil programming
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
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Research Article Gastroenterology Immunology

Epithelial SLPI expression in severe inflammatory bowel disease relates to high IL-17 and neutrophil programming

Abstract

Heterogeneity in disease severity and treatment response in inflammatory bowel disease (IBD) likely evolves from individual differences in host-microbiota-immune interactions. Histological evaluation of intestinal biopsies is central to diagnosis, but histological parameters that define underlying immune mechanisms are limited. We investigated histological features that distinguish individual patient immune profiles in therapy-naive pediatric IBD patients (age 6–18 years) using biopsy immunohistochemistry and transcriptomics and plasma proteomics across two cohorts. High colonic epithelial expression of secretory leukocyte protease inhibitor (SLPI), a microbiota-induced regulator of epithelial function, occurred in IBD patients with high clinical disease activity and more severe endoscopic and microscopic disease activity. SLPI expression was related to increased neutrophil infiltration, transcriptomic signatures of activation, and genes known to associate with therapeutic resistance. High SLPI colocalized with high densities of IL-17–secreting cells and was associated with high plasma concentrations of Th17-related immune proteins. Additionally, patients with high intestinal SLPI had an intrinsically different immunotype, in which circulating neutrophils exhibited altered transcription of genes involved in neutrophil granule formation, phagocytosis, oxidative phosphorylation, and interferon signaling. Thus, high colonic SLPI expression at diagnosis associates with severe IBD, increased IL-17A–neutrophil pathway responses, and altered transcriptomic wiring of circulating neutrophils.

Authors

Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom

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Figure 1

SLPI expression is upregulated in the distal colon of Muc2–/– mice, and in the distal colon of wild-type mice during DSS-induced colitis.

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SLPI expression is upregulated in the distal colon of Muc2–/– mice, and ...
(A) Slpi mRNA expression was measured in the distal colonic tissue of Muc2-deficient (Muc2–/–) mice and wild-type littermates at 2, 4, and 8 weeks old. Bars represent the mean relative expression levels for multiple mice; P values were calculated using Wilcoxon’s rank sum test (A, D, and E). (B) SLPI protein expression was detected by immunohistochemistry (IHC) in the distal colonic tissue of Muc2–/– mice and wild-type littermates at 2, 4, and 8 weeks old. Representative images were acquired at ×20 magnification. (C–F) Wild-type mice received 2% DSS in the drinking water for 5 subsequent days in 2 independent experiments. (C) Histological damage and inflammation were scored on a scale from 0 to 6 on H&E-stained sections of the distal colon. (D) Slpi mRNA expression was measured in the distal colon of untreated mice and at day 5, day 10, and day 36 of DSS treatment. (E) SLPI protein excretion was measured in fecal samples collected on day 1 until day 10 of DSS treatment. Shown are SLPI protein levels relative to total protein levels for mice from which fecal samples were available on that day. Bars represent the mean relative SLPI protein levels for multiple mice. (F) SLPI protein expression was detected by IHC in the distal colon of untreated mice and at day 5, day 10, and day 36 of DSS treatment. Representative H&E and SLPI-immunostained images of the distal colon of 2 mice per condition; original magnification, ×10.