title: Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis.
abstract: Aberrant immune response and changes in the gut microflora are the main causes of inflammatory bowel disease (IBD). Peptidoglycan recognition proteins (Pglyrp1, Pglyrp2, Pglyrp3, and Pglyrp4) are bactericidal innate immunity proteins that maintain normal gut microbiome, protect against experimental colitis, and are associated with IBD in humans. Nucleotide-binding oligomerization domain 2 (Nod2) is an intracellular bacterial sensor and may be required for maintaining normal gut microbiome. Mutations in Nod2 are strongly associated with Crohn's disease, but the causative mechanism is not understood, and the role of Nod2 in ulcerative colitis is not known. Because IBD is likely caused by variable multiple mutations in different individuals, in this study, we examined the combined role of Pglyrp3 and Nod2 in the development of experimental colitis in mice. We demonstrate that a combined deficiency of Pglyrp3 and Nod2 results in higher sensitivity to dextran sodium sulfate-induced colitis compared with a single deficiency. Pglyrp3(-/-)Nod2(-/-) mice had decreased survival and higher loss of body weight, increased intestinal bleeding, higher apoptosis of colonic mucosa, elevated expression of cytokines and chemokines, altered gut microbiome, and increased levels of ATP in the colon. Increased sensitivity to dextran sodium sulfate-induced colitis in Pglyrp3(-/-)Nod2(-/-) mice depended on increased apoptosis of intestinal epithelium, changed gut microflora, and elevated ATP. Pglyrp3 deficiency contributed colitis-predisposing intestinal microflora and increased intestinal ATP, whereas Nod2 deficiency contributed higher apoptosis and responsiveness to increased level of ATP. In summary, Pglyrp3 and Nod2 are both required for maintaining gut homeostasis and protection against colitis, but their protective mechanisms differ.
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, IN 46408; and.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Jing
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, IN 46408; and.
authors.forename: Fareeha
authors.initials: F
authors.lastname: Zulfiqar
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, IN 46408; and.
authors.forename: Shin Yong
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, IN 46408; and rdziar@iun.edu dgupta@iun.edu.
authors.forename: Roman
authors.initials: R
authors.lastname: Dziarski
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, IN 46408; and rdziar@iun.edu dgupta@iun.edu.
authors.forename: Dipika
authors.initials: D
authors.lastname: Gupta
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005260:Female; D007249:Inflammation / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D064307:Microbiota; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C118897:peptidoglycan recognition protein; D000255:Adenosine Triphosphate; D016264:Dextran Sulfate; D053148:Caspase 3
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