PTK6 regulates secretory cell production and innate immunity in a sex-dependent manner in the intestine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243229 | GEO | 2024/08/01
REPOSITORIES: GEO
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Project description:Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differential Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens.
2022-11-04 | GSE217040 | GEO
Project description:Succinate administration induced characteristic type 2 immunity via the tuft cell-ILC2 immune circuit, significantly ameliorating DSS-induced colonic inflammation by enhancing bactericidal capacity, reducing intestinal permeability, and modulating cytokine profiles in the colon. Succinate promoted expansion of myeloid cells in peripheral blood, mesenteric lymph nodes (MLN), and colonic lamina propria. The protective effect of succinate was abolished in Ccr2-/- mice but maintained in Rag1-/- mice. Adoptive transfer of monocytes from succinate-treated donors to naïve recipient mice mitigated intestinal inflammation. RNA-seq revealed increased expression of proinflammatory cytokines IL-1β, IL-6, and lactate upon lipopolysaccharide (LPS) stimulation in monocytes from succinate-treated mice. Moreover, the critical role of the IL-4Rα/Hif-1α axis in succinate-mediated protection was delineated.
2024-02-28 | GSE255272 | GEO
Project description:Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of breast cancer patients; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of TNBC remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e. via knock-out or add-back) had little effect on primary tumor volume but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor-stimulated cell motility relative to SH3-del, KM or wild-type PTK6 controls. Reverse phase protein array (RPPA) revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model. Together, these studies reveal that the SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC and identify RhoA and AhR as novel therapeutic targets in PTK6+ breast tumors.
2020-08-31 | GSE156676 | GEO
Project description:Tuft cells are an epithelial cell subset critical for initiating type 2 immune responses to parasites and protozoa in the small intestine. To respond to these stimuli, intestinal tuft cells use taste chemosensory signaling pathways, but the role of taste receptors in type 2 immunity is poorly understood. Here, we show that the taste receptor TAS1R3, which detects sweet and umami in the tongue, also regulates tuft cell responses in the distal small intestine. BALB/c mice, which have an inactive form of TAS1R3, as well as Tas1r3-deficient C57BL6/J mice both have severely impaired responses to tuft cell-inducing signals in the ileum including the protozoa Tritrichomonas muris and succinate. In contrast, TAS1R3 is not required to mount an immune response to the helminth Heligmosomoides polygyrus, which infects the proximal small intestine. Examination of uninfected Tas1r3-/- mice revealed a modest reduction in the number of tuft cells in the proximal small intestine but a severe decrease in the distal small intestine at homeostasis. Together, these results suggest that TAS1R3 influences intestinal immunity by shaping the epithelial cell landscape at steady state.
2020-01-09 | GSE140395 | GEO
Project description:Intestinal homeostasis is dynamically coordinated by various types of epithelial cells fulfilling their specific functions. Tuft cells as chemosensory cells have emerged as key players of the host response, such as innate immunity. Tuft cells are also critical for the restoration of intestinal architecture upon damage, thereby contributing to inflammatory bowel diseases (IBDs) characterized by defective intestinal barrier integrity. However, the molecular mechanism of how tuft cell homeostasis is controlled remains obscure. Recent studies have identified single-nucleotide polymorphisms in the inositol polyphosphate multikinase (IPMK) gene associated with IBD predisposition. IPMK, an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. To investigate the functional significance of IPMK in gut epithelium, we generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMKΔIEC) mice. Whereas IPMKΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis, with higher clinical colitis scores, and elevated epithelial barrier permeability. Surprisingly, no apparent defects in epithelial growth signaling pathway and inflammation were found in DSS-challenged, IPMK-deficient colons. Rather, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other intestinal epithelial cells. Ipmk deletion in the gut epithelium was found to reduce choline acetyltransferase but not cytokines (e.g., IL-25), suggesting selective loss of cholinergic signaling. Single-cell RNA-sequencing of mouse colonic tuft cells (EpCAM+/Siglec F+) and immunohistochemistry revealed three populations of tuft cells and further showed that, in IPMKΔIEC mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased, supporting the abnormal development of tuft cells without IPMK functions. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.
2022-10-26 | GSE200284 | GEO
Project description:Intestinal tuft cells are critical in anti-helminth immunity by producing IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) in order to ultimately expand both goblet and tuft cells. Translational reprogramming is involved in intestinal tuft cell differentiation but the role of tRNA modifications in this process is unknown. We show here that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of N. brasiliensis infection in mice. Elp3 is essential for the IL-13-dependent induction of some glycolytic enzymes such as Hexokinase 1 and Aldolase A and consequently links specific metabolic pathways to tuft cell differentiation. Importantly, loss of epithelial Elp3 in the intestine blocks the translation of Nprl2, a mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in both transit amplifying and progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation and impairs the control of intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cell differentiation and provide insights into mechanisms through which some tRNA modifications promote a type 2 immune response to parasites in the intestine.
2024-07-25 | GSE241625 | GEO
Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145827 | GEO
Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145828 | GEO
Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145829 | GEO
Project description:PTK6 regulates secretory cell production and innate immunity in a sex-dependent manner in the intestine
| PRJNA1017442 | ENA