Previous studies from this group showed that mouse IECs acquired tolerance following exposure to lipopolysaccharide (LPS) immediately after vaginal delivery and this correlated with a downregulation of IRAK1 expression by these cells. In this current study, the authors found that although IRAK1 protein levels in IECs were downregulated shortly after birth, Irak1 mRNA levels remained the same. In addition, IRAK1 protein levels were restored at the time of weaning (day 21 after birth). Expression of miR-146a was upregulated in IECs from wild-type but not TLR4-deficient neonates soon after birth and declined during week 3 after birth. Inhibition of miR-146a expression in neonates reversed IRAK1 protein downregulation in IECs and rendered the cells susceptible to apoptosis following oral challenge with bacteria. So, TLR4 signalling induces miR-146a expression soon after birth, and this results in translational inhibition of IRAK1, thereby protecting neonatal IECs from apoptosis. Further analysis showed that this pathway also induced the expression of a distinct set of genes in neonatal IECs with roles in cell survival, differentiation and homeostasis.
What is the signal that maintains IRAK1 downregulation during the neonatal period? Treatment of IECs from 10-day-old neonates with proteasome and lysosome inhibitors resulted in a rapid increase in IRAK1 protein levels in the absence of exogenously added LPS. Further analysis showed that LPS that was orally administered to neonates 2 hours after birth could be visualized within IECs isolated on day 1 up to day 14 after birth. Small interfering RNA (siRNA)-mediated depletion of TLR4 in neonates resulted in increased IRAK1 and reduced miR-146a expression in IECs. So, IEC tolerance during the neonatal period seems to be an active process involving miR-146a-associated degradation of IRAK1 in response to continuous TLR4 stimulation by intracellular LPS. Of note, siRNA-mediated knockdown of IRAK1 also reduced miR-146a levels in IECs, indicating that although most of the IRAK1 in these cells is degraded, a small amount is needed to maintain miR-146a expression.
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