DiscussionOur findings using Neu3-deficient mice indicate that Neu3 is required for the development of colitis in a mouse model of recurrent human food poisoning involving repeated transient ST infections during the adult lifespan. In the presence of Neu3, this repeated low titer infection regimen caused a progressive and enduring colitis linked to induction of neuraminidase activity in the small intestine contributed primarily by Neu3. A minor fraction of Neu activity was Neu3-independent, however its effect on IAP sialylation and regulation was negligible. Neu3 deficiency alone was sufficient to maintain the sialylation of nascent IAP and normalize IAP half-life at the enterocyte cell surface prior to IAP release into the lumen. In turn, the retention of normal IAP abundance in the intestinal lumen of Neu3-null mice was linked to lower levels of the pro-inflammatory IAP substrate LPS-phosphate in the colon with significant reductions of inflammatory cytokine RNA levels, leukocyte recruitment, and epithelial barrier erosion. This disease pathway points to Environmental and pathogenic triggers of intestinal inflammatory diseaseJamey D. MarthFigure 3. Figure 3. Molecular model of intestinal inflammation due to recurrent Gram-negative ST infectionIn the absence of infection of the small intestine, the anti-inflammatory GPI–linked IAP glycoprotein is highly expressed on the enterocyte cell surface. IAP is released into the lumen and travels through the intestinal tract to the colon where it dephosphorylates and detoxifies the LPS produced by Gram-negative commensal bacteria. Nascent IAP at the enterocyte cell surface undergoes a low rate of desialyation linked to the rate of internalization and degradation involving a normal mechanism of IAP aging and turnover in half-life determination. Enterocytes of the small intestine respond to LPS-phosphate and ST infection by activating TLR4 function, which induces host NEU3 neuraminidase on the enterocyte surface. Increased NEU3 activity accelerates the rate of IAP de-sialylation and internalization, reducing IAP abundance and resulting in increased levels of LPS-phosphate in the colon where TLR4 activation elicits inflammation and disease.and colitis. The molecular model of this process is shown in Figure 3. Our research with the Mizutani support was to determine if Neu3 was responsible for IAP desialylation and down modulation. Other neuraminidases including those of commensal origin, might possibly contribute. Our results now published reveal that Neu3-null mice are protected from the onset of severe colitis due to recurrent oral ST infections4). The data indicate that Neu3 plays a prominent role in the pathogenesis of colitis in this disease model, by desialylating nascent IAP and thereby causing IAP endocytic degradation and deficiency. Absence of Neu3 protects against IAP deficiency with reduced inflammation compared to wild-type littermates. The impact of Neu3 function on this mouse model of recurrent human food poisoning is profound and results in significant protection from disease. 76
元のページ ../index.html#76