Unité Propre de Recherche 9022 du Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67084 Strasbourg, Cedex, France.
Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2957-62. doi: 10.1073/pnas.1221910110. Epub 2013 Feb 1.
Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.
肠道慢性炎症对哺乳动物有害。同样，内源性菌群持续激活肠道免疫反应也被怀疑对果蝇有害。因此，果蝇肠道的先天免疫反应被严格控制，以同时防止病原微生物的感染和耐受内源性菌群。在这里，我们描述了编码多个膜相关 PDZ（PSD-95、Discs-large、ZO-1）结构域的 big bang（bbg）基因在调节肠道免疫反应中的作用。我们发现，在成年果蝇的中肠中，BBG 存在于隔膜连接处，在上皮细胞的顶端。在 bbg 缺失的情况下，这些连接处变得松动，使肠道菌群能够引发前肠固有免疫反应的持续激活。这种慢性上皮炎症导致 bbg 突变体果蝇的寿命缩短。用抗生素清除共生菌群可以防止肠道免疫反应的异常激活，并恢复正常寿命。我们现在提供了遗传证据，证明果蝇的隔膜连接是肠道免疫屏障的一部分，这一功能在哺乳动物中是保守的。总之，我们的数据表明，隔膜连接对于维持果蝇肠道中免疫耐受和免疫反应之间的微妙平衡是必要的，这为研究炎症性肠病提供了一个强大的模型。
