The innate regulatory protein NLRP12 maintains commensal bacterial symbiosis, and mitigates intestinal inflammation and obesity

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  • March 22, 2019
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  • Chen, Liang
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The nucleotide-binding domain, leucine-rich repeat containing proteins, also known as NOD-like receptors (NLRs), are pattern recognition receptors that play important roles in innate immunity (Aganna et al., 2002; Bertin et al., 1999; Harton et al., 2002; Hoffman et al., 2001; Inohara et al., 1999; Manji et al., 2002; Ting and Davis, 2005). Mounting evidence has expanded the known functions of innate immunity from the frontlines confronting infection to autoimmune and metabolic diseases. Therefore, studies on the function of NLRs have been extended to a much wider horizon, including transcriptional regulation (Bruchard et al., 2015), endoplasmic reticulum (ER) stress (Soares et al., 2014; Stokman et al., 2017), DNA damage repair (Hu et al., 2016; Wilson et al., 2015), protein ubiquitination (Abe et al., 2017; Allen et al., 2012b), and neurological disease (Lukens et al., 2015). Members of the NLR family can be categorized into two groups, the inflammasome-forming and non-inflammasome-forming NLRs. Inflammasomes are cytoplasmic multi-protein complexes that result in the catalytic cleavage of procaspase-1, generating caspase 1 necessary for the production of mature IL-1β and IL-18. These have been extensively studied due to their pro-inflammatory and anti-pathogen functions. However, mutations of non-inflammasome-forming NLRs, such as NLRP12 and NLRP14, have been reported to cause auto-inflammatory diseases (Abe et al., 2017; Allen, 2014; Borghini et al., 2011; Karki et al., 2016), which raises great interest in studying these non-inflammasome-forming NLRs (Allen, 2014; Ting et al., 2010). NLRP12, a negative regulator of innate immunity, suppresses colon inflammation and inflammation-driven colorectal cancer (Allen et al., 2012b; Zaki et al., 2011). Here, we identified that NLRP12 expression in mucosal tissue negatively correlates with colitis severity by performing gene expression analyses from multiple published colitis datasets. We also showed that exposure to commensal bacteria was required to differentiate colitis severity between WT and Nlrp12–/– mice, and the existence of commensal bacteria caused more basal inflammation attributed to the NLRP12-deficient hematopoietic cell components (such as CD11c+ macrophages and DCs). Meanwhile, this elevated basal inflammation promoted a dysbiotic microbiota manifested by the loss of diversity and protective stains, but increased abundance of colitogenic strains in the Nlrp12–/– mice. In this fashion, both the genetic defects of NLRP12 and the consequent dysbiotic microbiota worked together to achieve cumulative pathology. Finally, we found reconstitution of the absent beneficial bacteria in the Nlrp12–/– mice by cohousing with WT mice or inoculation of Lachnospiraceae can attenuate colitis severity. In the second part, we extended our knowledge of NLRP12 to diet induced obesity. We found NLRP12 expression was lower in patients with higher body mass index (BMI), and Nlrp12–/– mice were more susceptible to high-fat-diet (HFD) induced obesity and were insulin tolerant. These observations coincided with excessive systemic inflammation fueled by HFD-feeding, the NLRP12 mutation, and a skewed gut microbiota composition. We also identified that the gut microbiota was required to accelerate the process of weight gain in the Nlrp12–/– mice, and restoration of the decreased beneficial strains by cohousing with WT mice or Lachnospiraceae inoculation can attenuate the progression of obesity and improve insulin sensitivity. We found Lachnospiraceae, which were reduced by HFD-feeding and Nlrp12-deficiency, might produce anti-inflammatory short-chain-fatty-acid (SCFA) to promote IL10 secretion. Accordingly, Lachnospiraceae treatment restricts obesity and improves insulin sensitivity by suppressing the systemic inflammation caused by HFD and Nlrp12-deficiency.
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Advisor
  • Damania, Blossom
  • Hansen, Jonathan
  • Ting, Jenny P.-Y.
  • Matsushima, Glenn
  • Carroll, Ian
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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