Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice

Nature Microbiology volume 2, Article number: 17056 (2017) Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bap180 in the midgut promotes resistance to Ecc15 infection but with unrestricted bacterial growth.
Figure 2: Intestinal Bap180 represses eiger expression and Eiger-induced intestinal epithelial obstruction.
Figure 3: Bap180 responds to IMD–Relish signalling in the gut.
Figure 4: Bap180 represses IMD–AMP signalling by directly contacting Relish.
Figure 5: Baf180 controls intestinal inflammatory response to C. rodentium infection in mice.
Figure 6: Bap180 regulates intestinal inflammatory homeostasis in response to gut flora.

Similar content being viewed by others

References

  1. Garrett, W. S., Gordon, J. I. & Glimcher, L. H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ryu, J. H. et al. Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science 319, 777–782 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Buchon, N., Broderick, N. A. & Lemaitre, B. Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nat. Rev. Microbiol. 11, 615–626 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Apidianakis, Y. & Rahme, L. G. Drosophila melanogaster as a model for human intestinal infection and pathology. Dis. Model. Mech. 4, 21–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kaneko, T. et al. PGRP-LC and PGRP-LE have essential yet distinct functions in the Drosophila immune response to monomeric DAP-type peptidoglycan. Nat. Immunol. 7, 715–723 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Erturk-Hasdemir, D. et al. Two roles for the Drosophila IKK complex in the activation of relish and the induction of antimicrobial peptide genes. Proc. Natl Acad. Sci. USA 106, 9779–9784 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stoven, S. et al. Caspase-mediated processing of the Drosophila NF-κB factor relish. Proc. Natl Acad. Sci. USA 100, 5991–5996 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guo, L., Karpac, J. & Tran, S. L. & Jasper, H. PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan. Cell 156, 109–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Chen, H., Zheng, X. & Zheng, Y. Age-associated loss of lamin-B leads to systemic inflammation and gut hyperplasia. Cell 159, 829–843 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Paredes, J. C., Welchman, D. P., Poidevin, M. & Lemaitre, B. Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35, 770–779 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Libert, S., Chao, Y., Chu, X. & Pletcher, S. D. Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NFκB signaling. Aging Cell 5, 533–543 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Maillet, F., Bischoff, V., Vignal, C., Hoffmann, J. & Royet, J. The Drosophila peptidoglycan recognition protein PGRP-LF blocks PGRP-LC and IMD/JNK pathway activation. Cell Host Microbe 3, 293–303 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Zhao, H. W., Zhou, D. & Haddad, G. G. Antimicrobial peptides increase tolerance to oxidant stress in Drosophila melanogaster. J. Biol. Chem. 286, 6211–6218 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Mohrmann, L. et al. Differential targeting of two distinct SWI/SNF-related Drosophila chromatin-remodeling complexes. Mol. Cell. Biol. 24, 3077–3088 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bonnay, F. et al. Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling. EMBO J. 33, 2349–2362 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Basset, A. et al. The phytopathogenic bacteria erwinia carotovora infects Drosophila and activates an immune response. Proc. Natl Acad. Sci. USA 97, 3376–3381 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Carrera, I., Zavadil, J. & Treisman, J. E. Two subunits specific to the PBAP chromatin remodeling complex have distinct and redundant functions during Drosophila development. Mol. Cell. Biol. 28, 5238–5250 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

  20. Zeidler, M. P. et al. Temperature-sensitive control of protein activity by conditionally splicing inteins. Nat. Biotechnol. 22, 871–876 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Bae, Y. S., Choi, M. K. & Lee, W. J. Dual oxidase in mucosal immunity and host–microbe homeostasis. Trends Immunol. 31, 278–287 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Ha, E. M., Oh, C. T., Bae, Y. S. & Lee, W. J. A direct role for dual oxidase in Drosophila gut immunity. Science 310, 847–850 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ha, E. M. et al. Regulation of DUOX by the Gαq-phospholipase Cβ-Ca2+ pathway in Drosophila gut immunity. Dev. Cell 16, 386–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Lemaitre, B. et al. Functional analysis and regulation of nuclear import of dorsal during the immune response in Drosophila. EMBO J. 14, 536–545 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Igaki, T. & Miura, M. The Drosophila TNF ortholog Eiger: emerging physiological roles and evolution of the TNF system. Semin. Immunol. 26, 267–274 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Bonnay, F. et al. Big bang gene modulates gut immune tolerance in Drosophila. Proc. Natl Acad. Sci. USA 110, 2957–2962 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Igaki, T. et al. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 21, 3009–3018 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adachi-Yamada, T. et al. P38 mitogen-activated protein kinase can be involved in transforming growth factor beta superfamily signal transduction in Drosophila wing morphogenesis. Mol. Cell. Biol. 19, 2322–2329 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hay, B. A., Wolff, T. & Rubin, G. M. Expression of baculovirus P35 prevents cell death in Drosophila. Development 120, 2121–2129 (1994).

    CAS  PubMed  Google Scholar 

  31. Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Zaidman-Remy, A. et al. The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection. Immunity 24, 463–473 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Lhocine, N. et al. PIMS modulates immune tolerance by negatively regulating Drosophila innate immune signaling. Cell Host Microbe. 4, 147–158 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Kleino, A. et al. Pirk is a negative regulator of the Drosophila Imd pathway. J. Immunol. 180, 5413–5422 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Aggarwal, K. et al. Rudra interrupts receptor signaling complexes to negatively regulate the IMD pathway. PLoS Pathog. 4, e1000120 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mundy, R., MacDonald, T. T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697–1706 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Georgel, P. et al. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Yang, Y., Hou, L., Li, Y., Ni, J. & Liu, L. Neuronal necrosis and spreading death in a Drosophila genetic model. Cell Death Dis. 4, e723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Moshkin, Y. M., Mohrmann, L., van Ijcken, W. F. & Verrijzer, C. P. Functional differentiation of SWI/SNF remodelers in transcription and cell cycle control. Mol. Cell. Biol. 27, 651–661 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Tartey, S. et al. Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex. EMBO J. 33, 2332–2348 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fang, F. et al. Proinflammatory stimuli engage Brahma related gene 1 and Brahma in endothelial injury. Circ. Res. 113, 986–996 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tian, W. et al. Brahma-related gene 1 bridges epigenetic regulation of proinflammatory cytokine production to steatohepatitis in mice. Hepatology 58, 576–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Jin, Y. et al. Brahma is essential for Drosophila intestinal stem cell proliferation and regulated by hippo signaling. eLife 2, e00999 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wurster, A. L. et al. IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme. BMC Immunol. 13, 9 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Madison, B. B. et al. cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Ryu, J. H. et al. An essential complementary role of NF-κB pathway to microbicidal oxidants in Drosophila gut immunity. EMBO J. 25, 3693–3701 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rath, H. C. et al. Normal luminal bacteria, especially bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human β2 microglobulin transgenic rats. J. Clin. Invest. 98, 945–953 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rera, M., Clark, R. I. & Walker, D. W. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc. Natl Acad. Sci. USA 109, 21528–21533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gay, C., Collins, J. & Gebicki, J. M. Hydroperoxide assay with the ferric-xylenol orange complex. Anal. Biochem. 273, 149–155 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Leulier, F. et al. The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nature Immunol. 4, 478–484 (2003).

    Article  CAS  Google Scholar 

  53. Lee, T. I., Johnstone, S. E. & Young, R. A. Chromatin immunoprecipitation and microarray-based analysis of protein location. Nat. Protoc. 1, 729–748 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu, J. et al. MTMR4 attenuates transforming growth factor β (TGFβ) signaling by dephosphorylating R-Smads in endosomes. J. Biol. Chem. 285, 8454–8462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank J. Treisman (New York University), J.C. Pastor (Tsinghua University), T. Igaki (Kyoto University), M. Miura (The University of Tokyo), W.-j. Lee (Seoul National University), J.-L. Imler (University of Strasbourg) and F. Shao (National Institute of Biological Sciences, Beijing) for providing numerous reagents and valuable assistance, S. Zheng (Hainan Medical University) for pathological analysis and D. Li for discussions. This work was supported by grants from the National Natural Science Foundation of China to H.T. (81220108018) and L.P. (31370909, 31570897), the Ministry of Science and Technology of China to H.T. (2011CB946104) and L.P. (2012CB518900), the Novo Nordisk-Chinese Academy of Sciences Research Foundation to L.P. (NNCAS-2011-2) and the National Institute of Health of the USA to W.Z. (HL109054). L.P. is a fellow of the CAS Youth Innovation Promotion Association (2012083).

Author information

Author notes

  1. Hong Tang

    Present address: †Present address: Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031 China,

  2. Xiaomeng He and Junjing Yu: These authors contributed equally to this work

Authors and Affiliations

  1. CAS Key Laboratory of Infection and Immunity (CASKLII), Institute of Biophysics, 100101, Beijing, China

    Xiaomeng He, Junjing Yu, Shuo Yang, Lei Pan & Hong Tang

  2. Department of Gastroenterology, Xi'an Children's Hospital, 710006, Xi'an, China

    Min Wang, Yanan Han & Ying Fang

  3. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510000, Guangzhou, China

    Yang Cheng & Si-tang Gong

  4. College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China

    Shuo Yang & Guizhi Shi

  5. Core Facility for Protein Research, Institute of Biophysics, 100101, Beijing, China

    Guizhi Shi & Lei Sun

  6. Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Michigan, 48109, USA

    Zhong Wang

  7. The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Yang-Xin Fu

  8. Center for Precision Translational Medicine of Wuhan Institute of Virology and Guangzhou Women and Children's Medical Center, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China

    Hong Tang

Authors
  1. Xiaomeng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junjing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanan Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guizhi Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Si-tang Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yang-Xin Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hong Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.T. and L.P. designed the study. X.H. and J.Y. performed most of the experiments. X.H., J.Y., S.Y., S.-t.G., Y.-X.F. and L.P. collected and analysed the data. M.W., Y.H., Y.C., Y.F. and G.S. performed IHC analysis. L.S. prepared TEM samples. Z.W. helped to generate mice. H.T. and L.P. wrote the paper with contributions from all authors.

Corresponding authors

Correspondence to Lei Pan or Hong Tang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1–8, Supplementary Tables 1–7. (PDF 1468 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, X., Yu, J., Wang, M. et al. Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice. Nat Microbiol 2, 17056 (2017). https://doi.org/10.1038/nmicrobiol.2017.56

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/nmicrobiol.2017.56

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology