Tissue-layer-resolved proteome landscape of Crohn’s disease strictures highlights potential drivers of fibrosis progression
Johannes Alfredsson, Carina Sihlbom Wallem, Maja Östling, Hanna de la Croix, Elinor Bexe-Lindskog, Mary Jo Wick
Johannes Alfredsson, Carina Sihlbom Wallem, Maja Östling, Hanna de la Croix, Elinor Bexe-Lindskog, Mary Jo Wick
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Research Article Cell biology Gastroenterology

Tissue-layer-resolved proteome landscape of Crohn’s disease strictures highlights potential drivers of fibrosis progression

Abstract

The chronic inflammation of Crohn’s disease frequently leads to fibrosis and muscular hypertrophy of the intestinal wall. This often culminates in strictures, a serious condition lacking directed therapy. Severe pathological changes occur in the submucosa and muscularis propria intestinal wall layers of strictures, yet stricture-associated proteome changes in these layers is unexplored. We perform unbiased proteomics on submucosa and muscularis propria microdissected from transmural sections of strictured and nonstrictured ileum. Proteome changes in strictured submucosa reflected a transition from homeostasis to tissue remodeling, inflammation, and smooth muscle changes. Top submucosal features included reduced vascular components and lipid metabolism proteins accompanied by increased proteins with immune-, ECM-, or stress-related functions, including CTHRC1, TNC, IL-16, MZB1, and TXNDC5. In parallel, predominant changes in strictured muscularis propria included increased ECM (POSTN) and immune (mast cell CPA3) proteins alongside decreased proteins with lipid metabolic, mitochondrial, or key muscle functions. Finally, trends of differentially expressed proteins along nonstrictured submucosa suggest progressive profibrotic tissue remodeling and muscle expansion as proximity to strictures increases. The comprehensive proteome map presented here offers tissue-layer-resolved insight into the stricture microenvironment and potential drivers of fibrotic disease, providing a valuable resource to fuel biomarker and therapeutic target research.

Authors

Johannes Alfredsson, Carina Sihlbom Wallem, Maja Östling, Hanna de la Croix, Elinor Bexe-Lindskog, Mary Jo Wick

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Figure 9

ER-, ECM-, and muscle-associated proteins are characterized by progressively increased expression with proximity to STR tissue.

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ER-, ECM-, and muscle-associated proteins are characterized by progressi...
The figure shows subsets of combined-level DE proteins in the SM layer that progressively increase (70 proteins; A–D) with proximity to the stricture (Supplemental Methods 10, Trend analysis). (A) Scatter plots showing the expression level in Dist (y axis) and Adj (x axis) relative to the CTRL–STR range (CTRL = 0; STR = 1; dashed square). Due to this scaling, any dot (protein) in the coordinate system will correspond to a unique trend: CTRL = 0, Dist = y, Adj = x, STR = 1. The dashed square is divided into 16 numbered boxes to facilitate reference of each protein to the corresponding box in B to approximate a protein’s expression pattern based on its coordinates. The proteins (dots) are colored by category as in B. Dot size reflects the –log10(merged P value) from the AdjvCTRL comparison and serves as an indicator of the separation of Adj from CTRL. Ellipses highlight proteins with notable progressive DE patterns, including top-ranked ER proteins (violet), ECM-associated proteins (brown), and a separate group of ECM- and muscle-associated proteins (pink ellipse). (C and D) Dot plots of normalized abundance (log2 scale), adjusted for TMT set, from SM TMT-MS data across refined tissue types for selected labeled proteins in A. Horizontal bars mark the mean. Protein names are colored according to protein category in A and B. Dot color corresponds to the proximity key below the plots. Corresponding plots from the TIMS-TOF-MS data are shown in Supplemental Figure 11 as validation. See Supplemental Figure 11 for details.