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With substantially enhanced TLR4 in the intestine compared with sufferers that With drastically enhanced TLR4 in the intestine compared with patients that don't develop NEC, at comparable gestational ages [106]. We'll now explore in some detail the mechanisms by which TLR4 signaling within the intestinal epithelium results in the development of NEC.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptTLR4 regulation of intestinal injury and repair within the newborn gutJilling et al. reported in 2006 that the TLR4 mutant C3H/HeJ mice are protected from the development of NEC [128], however the precise mechanisms by which TLR4 acted to mediate NEC, and certainly, a direct link among TLR4 and the development of intestinal inflammation, remained unproven. We confirmed Jilling's findings in C3H/HeJ mice [106], too as in TLR4 knockout mice [66, 135]. In searching for to understand the mechanisms involved, we demonstrated that TLR4 activation leads to an increase in enterocyte apoptosis along with a reduction in enterocyte proliferation and migration in the premature intestine, which promotes intestinal injury and reduces the capacity of mucosal repair [106, 138, 139]. TLR4 activation was discovered to drastically inhibit enterocyte proliferation inside the ileum of newborn mice, but not of adult mice [135]. In additional research, we located that TLR4 signaling withinPathophysiology. Author manuscript; out there in PMC 2015 February 01.Lu and HackamPageenterocytes leads to the phosphorylation of glycogen synthase kinase 3 and inhibition from the -catenin signaling pathway, which ultimately decreased the extent of enterocyte proliferation [135]. In focusing around the significant cells that mediate replenishment in the injured mucosa, we determined that TLR4 is expressed on the surface of Leucine-rich repeat-containing G protein-coupled receptor 5-positive intestinal stem cells, and more interestingly, TLR4 activation causes decreased proliferation and improved apoptosis in intestinal stem cells [138]. Such an impairment of intestinal stem cell proliferation and number by TLR4 was found to be dependent on the activation of p53-up-regulated modulator of apoptosis, a crucial mediator of p53-dependent and p53-independent apoptosis [140, 141], which prevented cell division [138]. In addition to deleterious effects on apoptosis and proliferation, TLR4 activation also causes a reduction in enterocyte migration [106, 142]. Enterocytes migrate up toward the villus tip or across a wound, giving a protective mechanism to repair minor mucosal damages [143]. Around the contrary, disruption in enterocyte migration markedly reduces intestinal repair and regeneration [144], and exposure of enterocytes to LPS leads to substantially decreased enterocyte migration resulting from an increase in focal adhesion kinase-dependent cell matrix adhesiveness [106, 121, 142, 144]. In searching for to understand the mechanisms by which TLR4 activation can impair enterocyte migration, we've got shown that TLR4 signaling leads to a marked induction of autophagy inside the intestinal epithelium, which is needed for the impaired migration to occur [126]. The premature intestine in human and mice showed improved autophagy genes compared with mature intestine, and also the improved enterocyte autophagy is needed for NEC improvement, as mice lacking the autophagy gene autophagy-related protein 7 in the intestinal epithelium didn't create NEC as compared to wild-type mice [126]. TLR4 induced autophagy causes impairment in enterocyte migration inside a mechanism which needs activatio.