Sanchez Alvarez Rocio, Montalban-Arques Ana, Morsy Yasser, Gottier Claudia, Häfliger Janine, Atrott Kirstin, Bircher Anna, Katkeviciute Egle, Pöhlmann Doris, Linzmeier Luise, Determann Madita, Mamie Céline, Niechcial Anna, Schwarzfischer Marlene, Zeissig Sebastian, Lang Silvia, Scharl Michael, Spalinger Marianne
Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Medicine I, Center for Regenerative Therapies Dresden (CRTD), University Medical Center Dresden, Technische Universität (TU) Dresden, Dresden, Germany.
J Crohns Colitis. 2025 Feb 4;19(2). doi: 10.1093/ecco-jcc/jjaf016.
Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) regulates the internalization of growth factor receptors such as the epithelial growth factor receptor (EGFR). Given the crucial function of such receptors in intestinal epithelial cells (IECs), we assessed the involvement of PTPN23 in intestinal homeostasis and epithelial proliferation.
We generated mouse models with constitutive (PTPN23fl/flVilCre+/-) or inducible (PTPN23fl/flVilCreERT+/-) deletion of PTPN23 in IEC. To elucidate the functional consequences of PTPN23 deletion in IEC, we performed barrier function studies, flow cytometry, RNAseq, and in vivo experiments applying EGFR inhibition, antibiotic treatment, or co-housing approaches to further delineate the observed phenotype.
Deletion of PTPN23 in IECs resulted in a severe early-onset phenotype in both models. Mice were characterized by elongated colon, epithelial hyperproliferation, splenomegaly, and diarrhea leading to the death of the mice within 3 weeks of PTNP23 deletion. Compromised gut barrier integrity resulted in enhanced bacterial translocation accompanied by reduced IgA transcytosis in PTPN23fl/flVilCreERT+/- compared to wild-type mice. Although EGFR surface expression was increased upon PTPN23-deletion, inhibition of EGFR signaling did not prevent disease. In contrast, and in accordance with defective bacterial handling, antibiotic treatment, but not co-housing, fully rescued the phenotype.
The absence of PTPN23 in IECs leads to lethal dysregulation of intestinal homeostasis, triggered by bacterial infiltration due to defects in the intestinal epithelial barrier and impaired IgA transcytosis. Thus, we identify PTPN23 as a novel key player in preserving intestinal epithelial homeostasis, ultimately preventing bacterial overgrowth and excessive immune activation in the intestine.
非受体型蛋白酪氨酸磷酸酶23（PTPN23）调节上皮生长因子受体（EGFR）等生长因子受体的内化。鉴于此类受体在肠道上皮细胞（IECs）中的关键功能，我们评估了PTPN23在肠道稳态和上皮增殖中的作用。
我们构建了在IEC中组成性（PTPN23fl/flVilCre+/-）或诱导性（PTPN23fl/flVilCreERT+/-）缺失PTPN23的小鼠模型。为了阐明IEC中PTPN23缺失的功能后果，我们进行了屏障功能研究、流式细胞术、RNA测序，并采用EGFR抑制、抗生素治疗或同笼饲养方法进行体内实验，以进一步明确观察到的表型。
在两个模型中，IEC中PTPN23的缺失均导致严重的早发表型。小鼠的特征为结肠延长、上皮细胞过度增殖、脾肿大和腹泻，导致在PTNP23缺失后3周内死亡。与野生型小鼠相比，PTPN23fl/flVilCreERT+/-小鼠的肠道屏障完整性受损，导致细菌易位增加，同时IgA转胞吞作用降低。尽管PTPN23缺失后EGFR表面表达增加，但抑制EGFR信号并不能预防疾病。相反，与细菌处理缺陷一致，抗生素治疗而非同笼饲养完全挽救了表型。
IEC中缺乏PTPN23会导致肠道稳态的致命失调，这是由肠道上皮屏障缺陷和IgA转胞吞作用受损引起的细菌浸润所触发的。因此，我们确定PTPN23是维持肠道上皮稳态的一个新的关键因子，最终可防止肠道细菌过度生长和过度免疫激活。
