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Single-cell RNA Sequencing (scRNA−seq) Identifies L1CAM as a Key Mediator between Epithelial Tuft Cell and Innate Lymphoid Cell in the Colon of Hnrnp I Knockout Mice

ABSTRACT: (1) Background: Knockout (KO) of heterogeneous nuclear ribonucleoprotein I (Hnrnp I) in mouse intestinal epithelial cells (IECs) induced a severe inflammatory response in the colon, followed by hyperproliferation. This study aimed to investigate the epithelial lineage dynamics and cell–cell communications that underlie inflammation and colitis. (2) Methods: Single cells were isolated from the colons of wildtype (WT) and KO mice and used in scRNA−seq. Whole colons were collected for immunofluorescence staining and cytokine assays. (3) Results: from scRNA−seq, the number of DCLK1 + colonic tuft cells was significantly higher in the Hnrnp I KO mice compared to the WT mice. This was confirmed by immunofluorescent staining of DCLK1. The DCLK1 + colonic tuft cells in KO mice developed unique communications with lymphocytes via interactions between surface L1 cell adhesion molecule (L1CAM) and integrins. In the KO mice colons, a significantly elevated level of inflammatory cytokines IL4, IL6, and IL13 were observed, which marks type−2 immune responses directed by group 2 innate lymphoid cells (ILC2s). (4) Conclusions: This study demonstrates one critical cellular function of colonic tuft cells, which facilitates type−2 immune responses by com-municating with ILC2s via the L1CAM–integrins interaction. This communication promotes pro−inflammatory signaling pathways in ILC2, leading to the increased secretion of inflammatory cytokines.

ORGANISM(S): Mus musculus

PROVIDER: GSE245188 | GEO | 2023/10/14

REPOSITORIES: GEO

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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.

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Single-cell RNA Sequencing (scRNA−seq) Identifies L1CAM as a Key Mediator between Epithelial Tuft Cell and Innate Lymphoid Cell in the Colon of Hnrnp I Knockout Mice

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