ZnT2 Is Critical for TLR4-Mediated Cytokine Expression in Colonocytes and Modulates Mucosal Inflammation in Mice

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.

Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

“…In the small intestine, ZnT2 assumes a vital function in cytoplasmic zinc buffering, which is essential to Toll-like receptor 4 (TLR4) expression, initiation of pathogen-activated NF-κβ translocation, in addition to the release of cytokine in response to infectious challenges. 185 , 194 Furthermore, ZnT2 is indispensable for the development of lysosome biogenesis and bacterial-stimulated autophagy, 195 facilitating a powerful host defense and resolution machinery against enteric pathogens. In conclusion, this evidence suggests ZnT2 serves as an innovative modulator for mucosal inflammation in colonic cells and plays a crucial role in coping with infectious colitis, opening up possibilities on manipulating ZnT2 as a novel treatment strategy to particular intestinal infections.…”

“…In conclusion, this evidence suggests ZnT2 serves as an innovative modulator for mucosal inflammation in colonic cells and plays a crucial role in coping with infectious colitis, opening up possibilities on manipulating ZnT2 as a novel treatment strategy to particular intestinal infections. 194 ZIP8 is crucial for T cell activation, and recent studies have highlighted its significance in T cell function and innate immunity, which may have important implications in the context of inflammatory bowel disease (IBD). 145 , 196 In a study by Li et al, a novel association between Crohn’s disease (CD) and ZIP8 was identified.…”

Molecular Characterization of Zinc Transporter Proteins (ZnT) and the Roles in Diseases

“…Infants fed on maternal milk of ZnT2 gene-mutated mothers will occur serious zinc deficiency symptoms [5]. Moreover, recent research also shows that ZnT2 is related to gut dysbiosis and health in humans [6].…”

Unraveling the role of zinc transporters in healthy and respiratory disease challenged feedlot steers: Insights into zinc status assessment

“…ZnT2 plays an important role in mammary epithelial cells (MECS) as a Zn importer, and ZnT2 defects in mice lead to reduced milk Zn concentrations, mammary gland function, and milk production [78]. In the context of infection, deletion of ZnT2 in mice with enteric Citrobacter rodentium infection leads to reduced proinflammatory responses compared to wildtype (WT) mice due to a reduction in the expression of Toll-like receptor 4 (TLR4) on colonocytes [79]. Interestingly, Zn itself is shown to play a direct role in the regulation of TLR4 expression, as modest Zn chelation using N,N,N′,N′,-tetrakis (2pyridylmethyl)ethylenediamine (TPEN), a Zn chelator, increased the expression of TLR4, suggesting ZnT2 attenuation leads to the accumulation of cytosolic Zn, thus loss of TLR4 expression [79].…”

“…In the context of infection, deletion of ZnT2 in mice with enteric Citrobacter rodentium infection leads to reduced proinflammatory responses compared to wildtype (WT) mice due to a reduction in the expression of Toll-like receptor 4 (TLR4) on colonocytes [79]. Interestingly, Zn itself is shown to play a direct role in the regulation of TLR4 expression, as modest Zn chelation using N,N,N′,N′,-tetrakis (2pyridylmethyl)ethylenediamine (TPEN), a Zn chelator, increased the expression of TLR4, suggesting ZnT2 attenuation leads to the accumulation of cytosolic Zn, thus loss of TLR4 expression [79]. ZnT3 is primarily localized in synaptic vesicles, and the release of Zn in presynaptic vesicles modulates neuronal transmission and plasticity [80,81].…”