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Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection

Abstract

Despite the prevalence and clinical importance of influenza, its long-term effect on lung immunity is unclear. Here we describe that following viral clearance and clinical recovery, at 1 month after infection with influenza, mice are better protected from Streptococcus pneumoniae infection due to a population of monocyte-derived alveolar macrophages (AMs) that produce increased interleukin-6. Influenza-induced monocyte-derived AMs have a surface phenotype similar to resident AMs but display a unique functional, transcriptional and epigenetic profile that is distinct from resident AMs. In contrast, influenza-experienced resident AMs remain largely similar to naive AMs. Thus, influenza changes the composition of the AM population to provide prolonged antibacterial protection. Monocyte-derived AMs persist over time but lose their protective profile. Our results help to understand how transient respiratory infections, a common occurrence in human life, can constantly alter lung immunity by contributing monocyte-derived, recruited cells to the AM population.

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Fig. 1: At 1 month post-influenza, mice are more protected against S. pneumoniae infection and have an increased population of AMs that confer resistance.
Fig. 2: AMs from post-influenza mice produce increased IL-6 that confers protection from S. pneumoniae infection.
Fig. 3: CCR2-dependent monocyte recruitment contributes to the population of AMs and their altered functional profile 1 month after infection with influenza.
Fig. 4: Quantifying the contribution of CCR2-dependent monocytes to AMs and their cytokine production 1 month after infection with influenza.
Fig. 5: Recruited macrophages are distinct in their expression and chromatin profile, relative to resident macrophages, 1 month after infection with influenza.
Fig. 6: Following TLR stimulation, origin determines gene expression, chromatin profile and Il6 gene accessibility.
Fig. 7: Monocyte-derived AMs persist for 2 months after infection with influenza, but do not produce increased IL-6 and afford bacterial protection.

Data availability

Sequencing data are available in GEO under accession code GSE120543.

References

  1. Dahl, M. E., Dabbagh, K., Liggitt, D., Kim, S. & Lewis, D. B. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat. Immunol. 5, 337–343 (2004).

    CAS  PubMed  Google Scholar 

  2. Didierlaurent, A. et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J. Exp. Med. 205, 323–329 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Machiels, B. et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017).

    CAS  PubMed  Google Scholar 

  4. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Reese, T. A. et al. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response. Cell Host Microbe 19, 713–719 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kumar, A., Abdelmalak, B., Inoue, Y. & Culver, D. A. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir. Med. 6, 554–565 (2018).

    CAS  PubMed  Google Scholar 

  8. Bain, C. C. et al. Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat. Commun. 7, ncomms11852 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Misharin, A. V. et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 214, 2387–2404 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Shaw, T. N. et al. Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. J. Exp. Med. 215, 1507–1518 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  16. Soucie, E. L. et al. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 351, aad5510 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. Gibbings, S. L. et al. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood 126, 1357–1366 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).

    CAS  PubMed  Google Scholar 

  19. van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

    PubMed  Google Scholar 

  20. Halstead, E. S. et al. GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization. Respir. Res. 19, 3 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. Huang, F. F. et al. GM-CSF in the lung protects against lethal influenza infection. Am. J. Respir. Crit. Care Med. 184, 259–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sever-Chroneos, Z. et al. GM-CSF modulates pulmonary resistance to influenza A infection. Antivir. Res. 92, 319–328 (2011).

    CAS  PubMed  Google Scholar 

  23. GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).

    CAS  PubMed  Google Scholar 

  25. van der Poll, T. et al. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J. Infect. Dis. 176, 439–444 (1997).

    PubMed  Google Scholar 

  26. Plantinga, M. et al. Conventional and monocyte-derived CD11b+ dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).

    CAS  PubMed  Google Scholar 

  27. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    CAS  PubMed  Google Scholar 

  28. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Schneider, C. et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    CAS  PubMed  Google Scholar 

  32. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    CAS  PubMed  Google Scholar 

  33. Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    CAS  PubMed  Google Scholar 

  36. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Minutti, C. M. et al. Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356, 1076–1080 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, N. et al. Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity. J. Exp. Med. 216, 1291–1300 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schett, G. Physiological effects of modulating the interleukin-6 axis. Rheumatol. 57, ii43–ii50 (2018).

    CAS  Google Scholar 

  41. Hettinger, J. et al. Origin of monocytes and macrophages in a committed progenitor. Nat. Immunol. 14, 821–830 (2013).

    CAS  PubMed  Google Scholar 

  42. Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, 10–12 (2011).

    Google Scholar 

  43. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Karolchik, D. et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res. 32, D493–D496 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Li, H. et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  47. Kent, W. J., Zweig, A. S., Barber, G., Hinrichs, A. S. & Karolchik, D. BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics 26, 2204–2207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, Y. et al. Model-based analysis of ChIP-seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  49. Liao, Y., Smyth, G. K. & Shi, W. FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).

    CAS  PubMed  Google Scholar 

  50. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to S. Rose-John (Kiel University) for the kind gift of anti-IL-6, to C. Reis e Sousa and G. Stockinger for reading the manuscript and A. Warnatsch for initial help with reactive oxygen species measurements. This work benefited from data assembled by the ImmGen consortium. We thank the Advanced Sequencing, Flow Cytometry, Biological Research and Histopathology facilities of the Francis Crick Institute for excellent support. This study was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001206), the UK Medical Research Council (FC001206) and the Wellcome Trust (FC001206). Support by MRC grant U117597139 (S.C. and A.W.) and a BBSRC-GSK-funded case studentship BB/L502315/1 (H.A.) is gratefully acknowledged.

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H.A, S.C., J.K. and A.W. designed the experiments; H.A., J.K. and S.C. performed the experiments; H.A., J.K., S.C., H.P. and G.K. analyzed data; H.A., S.C., H.P., E.M.H., S.B. and A.W. interpreted data; M.M. provided vital reagents; S.C., H.P., E.M.H. and S.B. contributed to manuscript writing; H.A. and A.W. wrote the manuscript.

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Correspondence to Andreas Wack.

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E.M.H. and S.B. were employees of GSK at the time of this study. The other authors declare that they have no conflict of interest.

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Aegerter, H., Kulikauskaite, J., Crotta, S. et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol 21, 145–157 (2020). https://doi.org/10.1038/s41590-019-0568-x

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