Inflammatory bowel disease (IBD), consisting mainly of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. 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, I generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMK$^{ΔIEC}$) mice. Whereas IPMK$^{ΔIEC}$ mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis with higher epithelial damage. 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. Tuft cells are rare chemosensory cells in intestinal epithelium that not only mediate type 2 immune response but also support stem cell niche by paracrine signaling. 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 and immunohistochemistry revealed the heterogeneity of tuft cells and further showed that, in IPMK$^{ΔIEC}$ mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.
최근 이노시톨 다인산 멀티키나아제 유전자의 단일 염기 다형성이 염증성 장 질환의 발생과 연관이 있는 것으로 보고되어, 본 연구에서 이노시톨 다인산 멀티키나아제가 대장 상피 항상성 조절에 있어 어떠한 역할을 하는지 규명하고자 했다. 장 상피세포 특이적 이노시톨 다인산 멀티키나아제 녹아웃 생쥐를 이용, 해당 단백질이 결손된 상태에서 급성 장염을 유도하면 그 병증이 훨씬 악화됨을 관찰했다. 또한 장 상피세포 중 한 종류인 솔세포의 숫자가 감소했고, 그 중에서도 장 줄기세포에 콜린성 신호를 전달하여 그 활성을 유지하는 역할을 하는 특정 솔세포 군집의 비율을 감소시킴으로써 장염 상태에서의 회복을 저해한다는 사실을 유추했다. 이 결과는 이노시톨 다인산 멀티키나아제가 장 상피 항상성 유지에 필수적인 인자임을 시사한다.
