Browsing by Author "Holl, Eda K."
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- NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Q1 RegenerationMorrison, Holly A.; Eden, Kristin; Trusiano, Brie; Rothschild, Daniel E.; Qin, Yufeng; Wade, Paul A.; Rowe, Audrey J.; Mounzer, Christina; Stephens, Morgan C.; Hanson, Katherine M.; Brown, Stephan L.; Holl, Eda K.; Allen, Irving C. (Elsevier, 2024-06)BACKGROUND & AIMS: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-𝜅B-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/ differentiation via noncanonical NF-𝜅B signaling that is unique from canonical NF-𝜅B signaling. METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (Nik⁻/⁻) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium. RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-𝜅B signaling. In vitro studies evaluating Nik⁻/⁻ crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik⁻/⁻ cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik⁻/⁻ mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammationinduced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (NikΔCEC). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (NikΔMYE). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelAΔMYE) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelAΔCEC) CONCLUSIONS: Dysregulated noncanonical NF-𝜅B signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.
- The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancerAllen, Irving C.; TeKippe, Erin McElvania; Woodford, Rita-Marie T.; Uronis, Joshua M.; Holl, Eda K.; Rogers, Arlin B.; Herfarth, Hans H.; Jobin, Christian; Ting, Jenny P.-Y. (Rockefeller University Press, 2010-05-10)Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1Β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3-l- mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3-l- mice than in Pycard-l- or Casp1-l- animals. No significant differences were observed in disease progression or outcome in Nlrc4-l- mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
- Plexin-B2 and Plexin-D1 in Dendritic Cells: Expression and IL-12/IL-23p40 ProductionHoll, Eda K.; Roney, Kelly E.; Allen, Irving C.; Steinbach, Erin; Arthur, Janelle C.; Buntzman, Adam; Plevy, Scott; Frelinger, Jeffrey; Ting, Jenny P.-Y. (PLOS, 2012-08-15)Plexins are a family of genes (A,B,C, and D) that are expressed in many organ systems. Plexins expressed in the immune system have been implicated in cell movement and cell-cell interaction during the course of an immune response. In this study, the expression pattern of Plexin-B2 and Plexin-D1 in dendritic cells (DCs), which are central in immune activation, was investigated. Plexin-B2 and Plexin-D1 are reciprocally expressed in myeloid and plasmacytoid DC populations. Plasmacytoid DCs have high Plexin-B2 but low Plexin-D1, while the opposite is true of myeloid DCs. Expression of Plexin-B2 and Plexin-D1 is modulated upon activation of DCs by TLR ligands, TNFa, and anti-CD40, again in a reciprocal fashion. Semaphorin3E, a ligand for Plexin-D1 and Plexin-B2, is expressed by T cells, and interestingly, is dramatically higher on Th2 cells and on DCs. The expression of Plexins and their ligands on DCs and T cells suggest functional relevance. To explore this, we utilized chimeric mice lacking Plxnb2 or Plxnd1. Absence of Plexin-B2 and Plexin-D1 on DCs did not affect the ability of these cells to upregulate costimulatory molecules or the ability of these cells to activate antigen specific T cells. Additionally, Plexin-B2 and Plexin-D1 were dispensable for chemokine-directed in-vitro migration of DCs towards key DC chemokines, CXCL12 and CCL19. However, the absence of either Plexin-B2 or Plexin-D1 on DCs leads to constitutive expression of IL-12/IL-23p40. This is the first report to show an association between Plexin-B2 and Plexin-D1 with the negative regulation of IL-12/IL-23p40 in DCs. This work also shows the presence of Plexin-B2 and Plexin-D1 on mouse DC subpopulations, and indicates that these two proteins play a role in IL-12/IL-23p40 production that is likely to impact the immune response.