Biology subjects

Gao, J. Z.

Publications and source records attributed to Gao, J. Z..

2 recordsLinked to original sources

bioRxiv2024

An animal model for autoinflammation with infantile enterocolitis

Inflammasomes, particularly NLRC4, play a crucial role in immune responses to intracellular bacterial infections. However, gain-of-function mutations of NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). Existing mouse models do not adequately replicate the chronic, unprovoked inflammation observed in AIFEC patients. In this study, we developed a loxP-flanked NLRC4 V341A knock-in (KI) mouse model. Our global NLRC4 V341A KI mice exhibited symptoms closely mirroring those of human AIFEC. These mice demonstrated severe infantile enterocolitis, characterized by heightened intestinal inflammation, compromised intestinal barrier integrity, disrupted gut epithelium, and severe diarrhea, with high mortality within 10 days postnatally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1{beta}, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, adult NLRC4 conditional KI mice exhibited autoinflammation with only mild enterocolitis. Since AIFEC is characterized by life-threatening enterocolitis in infancy and recurrent severe autoinflammation throughout life, our conditional NLRC4 KI model effectively recapitulates the clinical features of human AIFEC. Moreover, the NLRC4 V341A-mediated monogenic infantile enterocolitis observed in our model resembles infantile-onset inflammatory bowel disease (IBD), positioning it as a valuable platform for research on very early-onset IBD.

immunology↗

bioRxiv2023

LRRK2 G2019S promotes the development of colon cancer via modulating intestinal inflammation

LRRK2 G2019S is the most prevalent variant associated with Parkinsons disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown. Using a mouse model of colitis-associated cancer (CAC) and LRRK2 G2019S knockin (KI) mice, here we report that LRRK2 G2019S promotes the pathogenesis of colon cancer as evidenced by increased tumor number and tumor size in LRRK2 G2019S KI mice. LRRK2 G2019S promoted intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, we found that LRRK2 G2019S KI mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis. Suppressing the kinase activity of LRRK2 ameliorated the severity of colitis in both LRRK2 G2019S KI and WT mice. At the molecular level, our investigation unveiled that LRRK2 G2019S promotes the production of reactive oxygen species, triggers inflammasome activation, and induces cell necrosis in the gut epithelium in a mouse model of colitis. Collectively, our data provide direct evidence that gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, implicating LRRK2 as a potential target in colon cancer patients with hyper LRRK2 kinase activity.

immunology↗