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3 recordsLinked to original sources
PubMed2024

Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.

LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.

Leucine-Rich Repeat Serine-Threonine Protein Kinas↗
PubMed2026

REG3α is a Predictive Biomarker of Complicated Disease from Preclinical through Established Crohn's Disease.

BACKGROUND: Regenerating islet-derived 3-alpha (REG3&#x3b1;) is a serum biomarker in patients with graft-versus-host disease (GVHD) linked to 6-month mortality. REG3&#x3b1; is produced by intestinal Paneth cells, which are implicated in Crohn's disease (CD) pathophysiology. OBJECTIVE: To assess associations between serum REG3&#x3b1; and progressive CD DESIGN: Serum REG3&#x3b1; was measured in two cross-sectional (M: Mount Sinai, L: Leuven) and a pre-diagnostic cohort (P: PREDICTS) with serial samples up to 10 years before CD diagnosis. Tissue REG3&#x3b1; expression was assessed via bulk RNA sequencing from paired ileal and colonic biopsies. Serum REG3&#x3b1; and tissue REG3&#x3b1; were associated with CD progression (hospitalization, surgery, steroid course, or new advanced therapy). Single-cell RNA sequencing data explored associations between REG3&#x3b1; expression, Paneth cell phenotypes, and CD. RESULTS: In 394 patients, high serum REG3&#x3b1; associated with CD progression, independent of C-reactive protein and endoscopic activity (M: HR 1.9 (95%CI 1.3-2.8); L: HR 2.9 (95%CI 1.9-4.6), both p<0.001). The association persisted in patients with mild or inactive CD. In the pre-diagnostic cohort, high serum REG3&#x3b1; predicted the development of CD, particularly complicated (B2/3) and surgical presentations, up to 10 years before diagnosis (P). Analysis of REG3&#x3b1; expression and Paneth cell transcriptomes suggested that CD is associated with loss of regenerative Paneth cell populations and enrichment in REG3&#x3b1;-expressing populations, suggesting a mechanism through which changes in serum REG3&#x3b1; associate with complicated CD. CONCLUSION: Serum REG3&#x3b1; holds potential as a non-invasive, prognostic biomarker in CD, independent of disease activity. High serum REG3&#x3b1;, even years before diagnosis, is linked to a complicated disease course.

Crohn&#x2019;s Disease↗
PubMed2012

Crohn's disease.

Crohn's disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders. Genome wide association studies identified susceptibility loci that--triggered by environmental factors--result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. We discuss the epidemiology, immunobiology, amd natural history of Crohn's disease; describe new treatment goals and risk stratification of patients; and provide an evidence based rational approach to diagnosis (ie, work-up algorithm, new imaging methods [ie, enhanced endoscopy, ultrasound, MRI and CT] and biomarkers), management, evolving therapeutic targets (ie, integrins, chemokine receptors, cell-based and stem-cell-based therapies), prevention, and surveillance.

Colonic Diseases↗