The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal ...physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
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•Liver-derived PEDF restrains ISC proliferation•The gut-liver axis calibrates PEDF production for ISC homeostasis•Microbial LPS regulates PEDF production via liver-derived PPARα•Fenofibrate enhances the susceptibility of intestinal inflammation via PEDF
The gut and liver reciprocally communicate to control gut homeostasis and tissue repair during health and diseases. Kim et al. demonstrate that liver-derived soluble factor pigment epithelium-derived factor (PEDF) restrains intestinal stem cell (ISC) expansion, suggesting that the gut-liver axis calibrates ISC fitness for intestinal homeostasis.
Peripheral regulatory T (pT
) cells are a key T cell lineage for mucosal immune tolerance and anti-inflammatory responses, and interleukin-2 receptor (IL-2R) signaling is critical for T
cell ...generation, expansion, and maintenance. The expression of IL-2R on pT
cells is tightly regulated to ensure proper induction and function of pT
cells without a clear molecular mechanism. We here demonstrate that Cathepsin W (CTSW), a cysteine proteinase highly induced in pT
cells under transforming growth factor-β stimulation is essential for the restraint of pT
cell differentiation in an intrinsic manner. Loss of CTSW results in elevated pT
cell generation, protecting the animals from intestinal inflammation. Mechanistically, CTSW inhibits IL-2R signaling in pT
cells by cytosolic interaction with and process of CD25, repressing signal transducer and activator of transcription 5 activation to restrain pT
cell generation and maintenance. Hence, our data indicate that CTSW acts as a gatekeeper to calibrate pT
cell differentiation and function for mucosal immune quiescence.
Excitation-contraction coupling in cardiomyocytes requires the proper targeting and retention of membrane proteins to unique domains by adaptor proteins like ankyrin-B. While ankyrin-B has been shown ...to interact with a variety of membrane and structural proteins located at different subcellular domains in cardiomyocytes, what regulates the specificity of ankyrin-B for particular interacting proteins remains elusive.
Here, we report the identification of two novel ankyrin-B isoforms AnkB-188 and AnkB-212 in human, rat, and mouse hearts. Novel cDNAs for both isoforms were isolated by long-range PCR of reverse-transcribed mRNA isolated from human ventricular tissue. The isoforms can be discriminated based on their function and subcellular distribution in cardiomyocytes. Heterologous overexpression of AnkB-188 increases sodium-calcium exchanger (NCX) membrane expression and current, while selective knockdown of AnkB-188 in cardiomyocytes reduces NCX expression and localization in addition to causing irregular contraction rhythms. Using an isoform-specific antibody, we demonstrate that the expression of AnkB-212 is restricted to striated muscles and is localized to the M-line of cardiomyocytes by interacting with obscurin. Selective knockdown of AnkB-212 significantly attenuates the expression of endogenous ankyrin-B at the M-line but does not disrupt NCX expression at transverse tubules in cardiomyocytes.
The identification and characterization of two functionally distinct ankyrin-B isoforms in heart provide compelling evidence that alternative splicing of the ANK2 gene regulates the fidelity of ankyrin-B interactions with proteins.
Background and Purpose
Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their ...actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 4‐(7,8,9,10‐tetrahydro‐5,7,7,10,10‐pentamethyl‐5H‐benzoenaphtho2,3‐b1,4diazepin‐13‐yl)benzoic acid, a selective antagonist of RARβ, is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain‐initiating cation channels.
Experimental Approach
We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch‐clamp recordings. We also used site‐directed mutagenesis of the channels to determine the structural basis of LE135‐induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135‐evoked pain‐related behaviours.
Key Results
LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin‐binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain‐related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135‐elicited pain‐related responses, as shown by pharmacological and genetic ablation studies.
Conclusions and Implications
This blocker of retinoid acid signalling also exerted non‐genomic effects through activating the pain‐initiating TRPV1 and TRPA1 channels.
Abstract only
Exposure of the inner esophageal epithelial layer to an acidic environment has long been held as a major component of gastroesophageal reflux disease. The study aimed to determine if ...TRPV4, a Ca2+‐permeable channel, and Ca2+ signaling may play a role in acid sensing as part of this process. Primary culture mouse esophageal keratinocytes were grown to confluency on coverslips and intracellular Ca2+, Ca2+i, monitored with the fluorescent indicator, Fura 2‐AM, via microscopic imaging. In control WT cells, addition of GSK1016 790A (30 nM), a selective TRPV4 agonist, or exposure of cells to hypotonic media, a stimulus known to activate TRPV4, induce a rapid elevation in Ca2+i. These responses were abolished in cells cultured from TRPV4 knockout mice, thereby demonstrating functional TRPV4 channels in the keratinocytes. In separate studies, cells exposed to low pH media showed little or no Ca2+i response to pH 6 media, a modest response to pH 5 media, and a strong response to pH 4 media. However, in cells cultured from TRPV4 knockout mice, the response to all pH states was largely abolished. We conclude that espophageal keratinocytes express TRPV4 and that this channel is activated by acidic pH (pH 4 – 5) and, thus, may be part of the mechanism underlining gastroesophageal reflux disease.
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