Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner

PLoS Pathog. 2021 Apr 27;17(4):e1009487. doi: 10.1371/journal.ppat.1009487. eCollection 2021 Apr.

Abstract

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • CD8-Positive T-Lymphocytes / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / virology
  • Female
  • Gastrointestinal Microbiome
  • Homeostasis
  • Humans
  • Immunity
  • Influenza, Human / immunology*
  • Influenza, Human / virology
  • Lipocalin-2 / genetics
  • Lipocalin-2 / metabolism*
  • Lung / immunology
  • Lung / virology
  • Lymphocyte Activation
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microbiota / immunology*
  • Specific Pathogen-Free Organisms
  • Transcriptome*

Substances

  • LCN2 protein, human
  • Lipocalin-2

Grant support

Funding was provided by the Austrian Science Fund (FWF, www.fwf.ac.at), DK Cell Communication in Health and Disease (W 1205-B09) and the Special Research Program Chromatin Landscapes (L-Mac: F 6104-B21) (to S.K.). P.S. acknowledges funding by the European Research Council (erc.europa.eu, Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 655153) and the Austrian Science Fund (FWF) (P31113-B30). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.