Complementary Roles of Nod2 in Hematopoietic and Nonhematopoietic Cells in Preventing Gut Barrier Dysfunction Dependent on MLCK Activity

Inflammatory Bowel Diseases
Ziad Al NabhaniFrederick Barreau

Abstract

Crohn's disease (CD) pathogenesis is multifactorial involving genetic and environmental factors. Loss of function mutations in the nucleotide oligomerization domain 2 (NOD2) gene are the main genetic risk factor for CD. Like patients with CD, Nod2 mice are characterized by an enhanced Th1 immune response and a defective mucosal barrier function evidenced by increased intestinal permeability. We previously showed that the latter is related to hematopoietic Nod2 deficiency. Our aim was to explore the mechanisms by which Nod2 expressed in the hematopoietic and in the nonhematopoietic compartments interplay to control epithelial paracellular permeability. Depletion of CD4 T cells in Nod2 mice and treatments with inhibitors were conducted in chimeric mice transplanted with bone marrow cells from Nod2-deficient donors into Nod2-sufficient recipients or vice versa. Caco-2 cells overexpressing a NOD2 gene which did or did not include a CD-associated polymorphism were treated with inhibitors or siRNAs and cocultured with hematopoietic cells from Peyer's patches. In vivo and in vitro Nod2 in hematopoietic cells regulates epithelial paracellular permeability through cytokine production influencing myosin light chain kinase (MLCK) activity...Continue Reading

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Citations

Feb 27, 2020·American Journal of Physiology. Endocrinology and Metabolism·Joseph F CavallariJonathan D Schertzer
Dec 1, 2019·Journal of Crohn's & Colitis·Ziad Al NabhaniJean-Pierre Hugot
Aug 1, 2019·Experimental and Therapeutic Medicine·Mengdie Shen, Li'Na Meng
May 24, 2020·International Journal of Molecular Sciences·Younggeon Jin, Anthony T Blikslager
Jul 23, 2020·Nature Metabolism·Ziad Al NabhaniGérard Eberl
Feb 21, 2021·Journal of Crohn's & Colitis·Núria Solà TapiasFrédérick Barreau

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