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 3

Colonic epithelial SLPI expression is associated with histological disease activity and with infiltration by calprotectin-positive cells.

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Colonic epithelial SLPI expression is associated with histological disea...
(A) H&E-stained sections of colonic biopsies from pediatric patients with CD (n = 41) or UC (n = 22) and IBD-negative (IBD-neg) controls (n = 15) were scored using the modified Global Histological Disease Activity Score (modified GHAS), including the subscore “activity GHAS.” GHAS scores are shown for the 3 categories of SLPI IHC scores. Kruskal-Wallis rank sum test. The size of the circles represents the number of biopsies (total n = 114 biopsies). (B and C) Calprotectin IHC in colonic biopsies from patients with CD or UC and IBD-negative controls. (B) Representative images of calprotectin IHC and SLPI IHC for colonic biopsies from 2 patients with CD and 2 patients with UC. Images were acquired at ×20 magnification. (C) The number of calprotectin-positive cells was counted per mm2 (maximum, 200) and grouped into 3 categories. Percentages of calprotectin scores per colonic SLPI IHC score (total n = 114 biopsies) are shown. Fisher’s exact test. For additional statistical comparisons, see Supplemental Table 2. (D) Heatmap of relationship between the different histological scores described above for all colonic biopsies (n = 114) from patients with CD (n = 40) or UC (n = 22) and IBD-negative controls (n = 15). Biopsies were ranked by SLPI IHC score, then by number of calprotectin-positive cells per mm2 (maximum, 200 “calprotectin IHC”), and then by modified GHAS. For each score, data are normalized to the minimum and maximum within that score. (E) SLPI, S100A8, and S100A9 mRNA expression measured by qPCR in ileal and colonic biopsies from patients with CD (n = 21) or UC (n = 19) and IBD-negative controls (n = 9). Each data point represents one biopsy. Spearman’s rank correlation coefficient.