Tanaka Toshiya, Tahara-Hanaoka Satoko, Nabekura Tsukasa, Ikeda Kaori, Jiang Shuying, Tsutsumi Shuichi, Inagaki Takeshi, Magoori Kenta, Higurashi Takuma, Takahashi Hirokazu, Tachibana Keisuke, Tsurutani Yuya, Raza Sana, Anai Motonobu, Minami Takashi, Wada Youichiro, Yokote Koutaro, Doi Takefumi, Hamakubo Takao, Auwerx Johan, Gonzalez Frank J, Nakajima Atsushi, Aburatani Hiroyuki, Naito Makoto, Shibuya Akira, Kodama Tatsuhiko, Sakai Juro
Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan.
Department of Immunology, Faculty of Medicine, Center for TARA and Japan Science and Technology Agency, CREST, University of Tsukuba, Tsukuba 305-8575, Japan.
Sci Rep. 2014 Jun 24;4:5412. doi: 10.1038/srep05412.
Macrophages are important for maintaining intestinal immune homeostasis. Here, we show that PPARβ/δ (peroxisome proliferator-activated receptor β/δ) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a-/- mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a-/- macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis.
巨噬细胞对于维持肠道免疫稳态至关重要。在此，我们表明过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）直接调控巨噬细胞中表达含免疫受体酪氨酸抑制基序（ITIM）受体的CD300a。在缺乏CD300a的小鼠中，高脂饮食（HFD）会导致慢性肠道炎症，伴有少量肠道淋巴毛细血管以及显著肿大的肠系膜淋巴结。因此，这些小鼠在高脂饮食时表现出甘油三酯吸收不良以及体重增加减少。高脂饮食的Cd300a - / - 小鼠的腹腔巨噬细胞呈经典的M1激活状态。脂多糖（LPS）激活Toll样受体4（TLR4）/髓样分化因子88（MyD88）信号通路会导致Cd300a - / - 巨噬细胞中白细胞介素-6（IL - 6）分泌延长。骨髓移植证实该表型源于白细胞中的CD300a缺陷。这些结果表明巨噬细胞中CD300a介导的抑制信号是肠道免疫稳态的关键调节因子。
