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Published on: April 21, 2015
ZnT2 Is Critical for TLR4-Mediated Cytokine Expression in Colonocytes and Modulates Mucosal Inflammation in Mice
Katherine McGourty1, Ramya Vijayakumar1, Tong Wu1
1Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, 3 Solomont Way, Weed Hall 302, Lowell, MA 01852, USA.
Abstract:
A wide range of microbial pathogens can enter the gastrointestinal tract, causing mucosal inflammation and infectious colitis and accounting for most cases of acute diarrhea. Severe cases of infectious colitis can persist for weeks, and if untreated, may lead to major complications and death. While the molecular pathogenesis of microbial infections is often well-characterized, host-associated epithelial factors that affect risk and severity of infectious colitis are less well-understood. The current study characterized functions of the zinc (Zn) transporter ZnT2 (SLC30A2) in cultured HT29 colonocytes and determined consequences of ZnT2 deletion in mice on the colonic response to enteric infection with Citrobacter rodentium. ZnT2 in colonocytes transported Zn into vesicles buffering cytoplasmic Zn pools, which was important for Toll-like receptor 4 (TLR4) expression, activation of pathogen-stimulated NF-κβ translocation and cytokine expression. Additionally, ZnT2 was critical for lysosome biogenesis and bacterial-induced autophagy, both promoting robust host defense and resolution mechanisms in response to enteric pathogens. These findings reveal that ZnT2 is a novel regulator of mucosal inflammation in colonocytes and is critical to the response to infectious colitis, suggesting that manipulating the function of ZnT2 may offer new therapeutic strategies to treat specific intestinal infections.
Insights
The zinc transporter ZnT2 is crucial for colon cells to fight gut infections. Deleting ZnT2 impairs host defense, highlighting its role in infectious colitis.
Area of Science:
- Microbiology
- Immunology
- Cell Biology
Background:
- Infectious colitis, often caused by gastrointestinal pathogens, leads to mucosal inflammation and acute diarrhea.
- While pathogen mechanisms are known, host epithelial factors influencing colitis severity are less understood.
- Zinc transporter ZnT2 (SLC30A2) function in colonocytes is largely uncharacterized.
Purpose of the Study:
- To characterize ZnT2 functions in HT29 colonocytes.
- To determine the impact of ZnT2 deletion on colonic response to *Citrobacter rodentium* infection in mice.
Main Methods:
- Studied ZnT2 in cultured HT29 colonocytes.
- Utilized a mouse model with ZnT2 deletion to assess response to enteric infection.
- Analyzed Toll-like receptor 4 (TLR4) expression, NF-κβ translocation, cytokine expression, lysosome biogenesis, and autophagy.
Main Results:
- ZnT2 transports zinc into vesicles, buffering cytoplasmic zinc levels in colonocytes.
- ZnT2 is essential for maintaining Toll-like receptor 4 (TLR4) expression.
- ZnT2 regulates pathogen-stimulated NF-κβ translocation and cytokine production.
- ZnT2 is critical for lysosome biogenesis and autophagy, enhancing host defense against enteric pathogens.
- ZnT2 deletion in mice exacerbates colonic inflammation and impairs pathogen clearance.
Conclusions:
- ZnT2 is a novel regulator of mucosal inflammation in colonocytes.
- ZnT2 plays a critical role in the host response to infectious colitis.
- Targeting ZnT2 function may offer new therapeutic strategies for intestinal infections.
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