COMMD1 Is an Inhibitor of Intestinal Inflammation and Colitis in a Myeloid-Specific Knockout Mouse Model
H Li, SD Melton, C Komarck, X Mao, B van de Sluis, C Wijmenga, LW Klomp, RM Genta, E Burstein. UT Southwestern Medical Center, Dallas, TX; Univ. of Michigan Medical School, Ann Arbor, MI; Univ. of Groningen, Groningen, Netherlands; Utrecht University, Utrecht, Netherlands
Background: Nuclear factor-kappa B (NF-κB) is a key transcriptional regulator of innate and adaptive immunity. NF-κB inhibition protects against chronic intestinal inflammation and necrotizing enterocolitis in animal models. The copper metabolism (Murr1) domain containing 1 gene (COMMD1) is a regulator of copper homeostasis, sodium uptake, and NF-κB. COMMD1 functions as an inhibitor of NF-κB mediated gene expression, but its relative contribution to the control of inflammation has not been studied in vivo up to this point. This study examines the role of Commd1 in intestinal inflammation and colitis in mice with myeloid-specific knockout of Commd1.
Design: Using the LysM-Cre transgene, twenty myeloid Commd1-deficient mice were generated by Cre-LoxP mediated recombination. Twenty six wild-type mice were studied as controls. Colitis was then induced using dextran sulfate sodium (DSS). The phenotypic effects were evaluated via disease activity index (DAI), colon length, and histopathology. The DAI included weight loss, rectal bleeding, and diarrhea. The histopathological score of colitis was derived by grading four categories (crypt loss, crypt distortion, inflammation, and hyperplastic epithelial changes) on a scale of 0-4.
Results: Loss of Commd1 in myeloid cells significantly worsened the course of DSS-induced colitis.
|Wild-type||Commd1 Knockout||T-test (p value)|
|DAI (au)||9.1||11.4||9.00 E-07|
|Weight (%)||85||77||7.00 E-06|
|Colon length (cm)||6.1||5.5||0.002|
|Histolpathology score (au)||2.83||3.7||0.04|