Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer

Cell Reports
Noa StettnerAyelet Erez

Abstract

Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.

Citations

Feb 7, 2019·Journal of Inherited Metabolic Disease·Julien BaruteauJohannes Häberle
Aug 8, 2018·Disease Models & Mechanisms·Rom Keshet, Ayelet Erez
Oct 9, 2019·Scientific Reports·Melanie A EshelmanGregory S Yochum
Jul 14, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Zhanling DingJinming Hu
Sep 9, 2018·Nature Reviews. Cancer·Rom KeshetAyelet Erez
Feb 12, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Yonger ChenShuxian Chen
Dec 30, 2020·The Journal of Clinical Investigation·Zixue JinBrendan Lee
Aug 8, 2020·Neurochemistry International·Yun ZhouNiels Christian Danbolt
Sep 2, 2021·Molecular Cell·Emma HajajAyelet Erez
Oct 3, 2021·Cell Death & Disease·Jonathan H M van der MeerVanesa Muncan

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Datasets Mentioned

BETA
GSE57945

Methods Mentioned

BETA
dissection
fluorescence-activated cell sorting
ELISA
FACS

Software Mentioned

Pro Pulse
R
AOM
Mantra
STATISTICA
Statsoft
DSS
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