DataSheet_1_CT-M8 Mice: A New Mouse Model Demonstrates That Basophils Have a Nonredundant Role in Lupus-Like Disease Development.pdf

Tissue-specific mouse models are essential tools to decipher the role of each cell compartment and/or their expressed genes in the pathophysiology of diseases. Here, we describe a new knock-in mouse model allowing expression of both the fluorescent protein tdTomato and the CRE recombinase selectively in the basophil compartment under the control of the Mcpt8 gene. These “CT-M8” mice did not show any abnormalities in their peripheral distribution of major immune cell populations nor their basophil function. CT-M8 mice allowed the identification of basophils by immunofluorescence and flow cytometry and basophil-specific Cre-mediated floxed gene deletion. Breeding of our CT-M8 mice with the ROSA26flox-stop-DTA mice led to the generation of basophil-deficient mice with no detectable abnormalities in other cell compartments. These mice were then used to document basophil involvement in systemic lupus erythematosus (SLE) pathophysiology since we previously reported by transient depletion of these cells during the course of an ongoing disease that they support and amplify autoantibody production in two distinct lupus-like mouse models (Lyn−/− and pristane-induced). Here, constitutive basophil deficiency prevented pristane-induced lupus-like disease development by limiting autoantibody titers and renal damages. Therefore, basophils have a nonredundant role in pristane-induced lupus-like disease and are involved in both its induction and amplification. This CT-M8 new mouse model will allow us to finely decipher the role of basophils and their expressed genes in health and disease.

组织特异性小鼠模型是解析疾病病理生理过程中各细胞区室及其表达基因功能的关键工具。本研究报道一种新型敲入小鼠模型，该模型可在Mcpt8基因的调控下，于嗜碱性粒细胞区室中特异性表达荧光蛋白tdTomato与CRE重组酶。该CT-M8小鼠的主要免疫细胞群外周分布及嗜碱性粒细胞功能均未出现异常。CT-M8小鼠可通过免疫荧光与流式细胞术实现嗜碱性粒细胞的鉴定，并可介导嗜碱性粒细胞特异性的floxed基因敲除。将本研究的CT-M8小鼠与ROSA26flox-stop-DTA小鼠杂交，可获得其他细胞区室无可见异常的嗜碱性粒细胞缺陷小鼠。鉴于本团队此前已在两种狼疮样小鼠模型（Lyn−/−及pristane诱导型）中报道，于疾病进程中暂时性耗竭嗜碱性粒细胞可促进并放大自身抗体的产生，因此本研究利用该类小鼠探究嗜碱性粒细胞在系统性红斑狼疮（SLE）病理生理过程中的作用。本研究中，组成型嗜碱性粒细胞缺陷可通过降低自身抗体滴度与减轻肾脏损伤，抑制pristane诱导型狼疮样疾病的发生发展。综上，嗜碱性粒细胞在pristane诱导型狼疮样疾病中发挥不可或缺的非冗余功能，并参与疾病的诱导与放大过程。该新型CT-M8小鼠模型将助力我们精准解析嗜碱性粒细胞及其表达基因在生理与病理过程中的功能。