Nature Microbiology 2, Article number: 17056 (2017)，doi:10.1038/nmicrobiol.2017.56, Received:24 March 2016, Accepted:14 March 2017, Published online:18 April 2017
Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice
Xiaomeng He1 n2, Junjing Yu1 n2, Min Wang2, Yang Cheng3, Yanan Han2, Shuo Yang1, 4, Guizhi Shi4, 5, Lei Sun5, Ying Fang2, Si-tang Gong3, Zhong Wang6, Yang-Xin Fu7, Lei Pan1 & Hong Tang1, 8 n1
Immune homeostasis is a prerequisite to protective immunity against gastrointestinal infections. In Drosophila, immune deficiency (IMD) signalling (tumour necrosis factor receptor/interleukin-1 receptor, TNFR/IL-1R in mammals) is indispensable for intestinal immunity against invading bacteria. However, how this local antimicrobial immune response contributes to inflammatory regulation remains poorly defined. Here, we show that flies lacking intestinal Bap180 (a subunit of the chromatin-remodelling switch/sucrose non-fermentable (SWI/SNF) complex) are susceptible to infection as a result of hyper-inflammation rather than bacterial overload. Detailed analysis shows that Bap180 is induced by the IMD–Relish response to both enteropathogenic and commensal bacteria. Upregulated Bap180 can feed back to restrain overreactive IMD signalling, as well as to repress the expression of the pro-inflammatory gene eiger (TNF), a critical step to prevent excessive tissue damage and elongate the lifespan of flies, under pathological and physiological conditions, respectively. Furthermore, intestinal targeting of Baf180 renders mice susceptible to a more aggressive infectious colitis caused by Citrobacter rodentium. Together, Bap180 and Baf180 serve as a conserved transcriptional repressor that is critical for the maintenance of innate immune homeostasis in the intestines.
The innate immune compartment of the intestinal mucosa provides a pivotal interface between symbiotic/pathogenic microorganisms and the host. Immune activation is required to resolve infections and restore homeostasis of the microbiota and intestinal epithelia1,2,3. However, excessive inflammation in the gut leads to dysfunction of the epithelial barrier and is causative of inflammatory bowel disease (locally) and even asthma and type I diabetes (systemically). A better understanding of innate immune homeostasis in the intestines is thus essential.
Drosophila melanogaster has been widely used to investigate intestinal innate immunity, because their mucosal structure and immune signalling are conserved in mammals3,4. The immune deficiency (IMD) pathway provides major local defence in fly guts. The diaminopimelic acid (DAP)-type peptidoglycan (PGN) of Gram-negative bacteria is sensed by PGN recognition receptor-LC (PGRP-LC) on the membrane or PGRP-LE in the cytoplasm, initiating the IMD signalling cascade5. Relish (p105-like NF-κB in mammals)6 is then phosphorylated and cleaved to release the Rel domain, which translocates to the nuclei to initiate the transcription of antimicrobial peptide (AMP) genes7,8. As dysregulated tumour necrosis factor/interleukin-1 (TNF/IL-1) signalling is often associated with hyper-inflammatory diseases in humans, unconstrained IMD signalling, especially in the gut9,10, also causes deteriorative inflammation and is life-threatening to flies11,12,13. Tightly controlled IMD signalling is thus needed to maintain the fitness of flies. Of note, although AMPs are considered the major effectors of IMD signalling, a hyper AMP response has little impact on fly survival14. Indeed, pro-inflammatory cytokines, in addition to AMPs, in response to IMD signalling merit further investigation.
In Drosophila, there are two Brahma-associated switch/sucrose non-fermentable (SWI/SNF)-like complexes, a Brahma-associated complex (BAP) with a unique Osa subunit and Polybromo-associated Brahma complex (PBAP) with Polybromo (Bap180) and Bap170 subunits. The equivalent P/BAP complexes in mammals are P/BAF (ref. 15). The BAP complex, but not PBAP, has been reported previously to activate IMD signalling in the fatbody16. However, whether the PBAP complex is involved in local defence has not been evaluated thoroughly. Recently, our pilot screening indicated that bap180 mutant flies were more susceptible to oral bacterial infection than wild-type flies, OrR. We show, here, that intestinal Bap180 is upregulated by IMD–Relish signalling and then functions as a transcription repressor independent of the PBAP complex to dampen the hyper-inflammatory response in the gut. Gene targeting of Baf180 in mice further supported its important role in maintaining intestinal immune homeostasis.