Abstract
Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (TfebΔIEC) to examine its importance in defense against injury. Unperturbed TfebΔIEC mice exhibited grossly normal intestinal epithelia, except for a defect in Paneth cell granules. TfebΔIEC mice exhibited lower levels of lipoprotein ApoA1 expression, which is downregulated in Crohn’s disease patients and causally linked to colitis susceptibility. Upon environmental epithelial injury using dextran sodium sulfate (DSS), TfebΔIEC mice exhibited exaggerated colitis. Thus, our study reveals that TFEB is critical for resistance to intestinal epithelial cell injury, potentially mediated by APOA1.
Highlights
The intestinal epithelium is the major site of interaction between the host and colonizing microbes
We discovered that transcription factor transcription factor EB (TFEB) is important for the induction of host defense genes in C. elegans infected with pathogenic bacteria[11]
We discovered that C. elegans HLH-30/TFEB controls the induction of genes with antimicrobial or cytoprotective functions, and that both classes of genes are required for host defense against infection
Summary
Intestinal epithelial TFEB is dispensable for baseline homeostasis. To determine the pattern of expression of TFEB in unperturbed animals, we performed anti-TFEB immunofluorescence in sections of the small intestine and colon of 8–12 week old mice of both sexes. QRT-PCR confirmed lower Defa[25] and Defa[26] expression in epithelial cells of TfebΔIEC animals compared to Tfebflox/flox animals at Day 11 after DSS treatment (Fig. 5B,C) These results support the hypothesis that TFEB is required for proper defensin gene expression after epithelial injury, and are consistent with the observed secretory granule defect at baseline and absence of Paneth cells after recovery in TfebΔIEC animals. The latter cluster exhibited enrichment of gene ontology annotation categories, which were related to adherens junctions, vesicle/vacuole/ lysosome, mitochondria, and the endoplasmic reticulum (Table S2) Taken together, these findings surprisingly showed no defect in the expression of lysosomal and autophagy genes in TfebΔIEC animals, and suggested that unknown cellular mechanisms may be activated to compensate for the loss of TFEB within intestinal epithelial cells. The arrows connecting TFEB to each gene/category are not meant to imply direct regulation
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