NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth

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  • Chen, Liang
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Wilson, Justin E.
    • Affiliation: University of North Carolina at Chapel Hill
    • Other Affiliation: Department of Genetics
  • Koenigsknecht, Mark J.
    • Other Affiliation: Department of Internal Medicine; Division of Infectious Diseases; University of Michigan
  • Chou, Wei-Chun
    • Affiliation: School of Medicine, Department of Genetics
  • Montgomery, Stephanie A.
    • Affiliation: University of North Carolina at Chapel Hill
    • Other Affiliation: Department of Pathology and Laboratory Medicine
  • Truax, Agnieszka D.
    • Affiliation: University of North Carolina at Chapel Hill
    • Other Affiliation: Department of Genetics
  • Brickey, W June
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Packey, Christopher D.
    • Other Affiliation: Division of Digestive and Liver Diseases; Columbia University Medical Center
  • Maharshak, Nitsan
    • Other Affiliation: Department of Gastroenterology; Tel-Aviv Sourasky Medical Center; Sackler Faculty of Medicine; Tel-Aviv University
  • Matsushima, Glenn K.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
    • Other Affiliation: School of Medicine
  • Plevy, Scott E.
    • Other Affiliation: Immunology Research and Development; Janssen Pharmaceuticals
  • Young, Vincent B.
    • Other Affiliation: Department of Internal Medicine; Division of Infectious Diseases; University of Michigan
  • Sartor, R Balfour
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Ting, Jenny P.-Y.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
    • Other Affiliation: University of North Carolina at Chapel Hill
Abstract
  • Inflammatory bowel diseases involve the dynamic interplay of host genetics, microbiome and inflammatory response. Here, we report that NLRP12, a negative regulator of innate immunity, is reduced in human ulcerative colitis by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12-deficiency in mice caused increased colonic basal inflammation, leading to a less-diverse microbiome, loss of protective gut commensal strains (Lachnospiraceae) and increased colitogenic strains (Erysipelotrichaceae). Dysbiosis and colitis susceptibility associated with Nlrp12-deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines or by administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from specific pathogen free reared mice into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contribute to immune signaling that culminates in colon inflammation. These findings reveal a feed-forward loop where NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12-deficiency can reverse dysbiosis.
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DOI
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Nature Immunology
Journal volume
  • 18
Journal issue
  • 5
Page start
  • 541
Page end
  • 551
Language
  • English
ISSN
  • 1529-2908
  • 1529-2916

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