👤 Tsutomu Toki

Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation. WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains. Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma. Show less

Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%). Show less