RESUMEN
The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Mucosa Intestinal/citología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina-17/metabolismo , Células Madre/metabolismo , Animales , Comunicación Celular , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran/efectos adversos , Humanos , Interleucina-17/metabolismo , Interleucina-17/farmacología , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/metabolismo , Intestinos/patología , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Receptores de Interleucina-17/deficiencia , Factor de Transcripción SOX9/metabolismo , Transducción de Señal , Células Madre/citologíaRESUMEN
SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance of proper ChC function is further underscored by the association of ChC connectivity defects with various neurological conditions. Despite this, the cellular mechanisms governing ChC axo-axonic synapse formation remain poorly understood. Here, we identify microglia as key regulators of ChC axonal morphogenesis and AIS synaptogenesis, and show that disease-induced aberrant microglial activation perturbs proper ChC synaptic development/connectivity in the neocortex. In doing so, such findings highlight the therapeutic potential of manipulating microglia to ensure proper brain wiring.