Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3

  1. Rémi Porte  Is a corresponding author
  2. Rita Silva-Gomes
  3. Charlotte Theroude
  4. Raffaella Parente
  5. Fatemeh Asgari
  6. Marina Sironi
  7. Fabio Pasqualini
  8. Sonia Valentino
  9. Rosanna Asselta
  10. Camilla Recordati
  11. Marta Noemi Monari
  12. Andrea Doni
  13. Antonio Inforzato
  14. Carlos Rodriguez-Gallego
  15. Ignacio Obando
  16. Elena Colino
  17. Barbara Bottazzi  Is a corresponding author
  18. Alberto Mantovani  Is a corresponding author
  1. IRCCS Humanitas Research Hospital, Italy
  2. University Hospital of Lausanne, Switzerland
  3. Humanitas University, Italy
  4. Fondazione Filarete, Italy
  5. University Fernando Pessoa Canarias, Spain
  6. Hospital Universitario Virgen del Rocío, Spain
  7. Complejo Hospitalario Universitario Insular Materno Infantil, Spain

Abstract

Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1β/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice presented more severe invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file. Source Data files have been provided for Figures 1, 2, 3, 4, 5, 6, 7 and 8 and supplementary figures.

Article and author information

Author details

  1. Rémi Porte

    IRCCS Humanitas Research Hospital, Milan, Italy
    For correspondence
    remi.porte@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8311-0202
  2. Rita Silva-Gomes

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Charlotte Theroude

    Infectious Diseases Service Laboratory, University Hospital of Lausanne, Epalinges, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Raffaella Parente

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Fatemeh Asgari

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Marina Sironi

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Fabio Pasqualini

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Sonia Valentino

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Rosanna Asselta

    Department of Biomedical Sciences, Humanitas University, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Camilla Recordati

    Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. Marta Noemi Monari

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  12. Andrea Doni

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Antonio Inforzato

    IRCCS Humanitas Research Hospital, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Carlos Rodriguez-Gallego

    Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
    Competing interests
    The authors declare that no competing interests exist.
  15. Ignacio Obando

    Department of Pediatrics, Hospital Universitario Virgen del Rocío, Sevilla, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4516-1735
  16. Elena Colino

    Department of Pediatrics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain
    Competing interests
    The authors declare that no competing interests exist.
  17. Barbara Bottazzi

    IRCCS Humanitas Research Hospital, Milan, Italy
    For correspondence
    Barbara.Bottazzi@humanitasresearch.it
    Competing interests
    The authors declare that no competing interests exist.
  18. Alberto Mantovani

    IRCCS Humanitas Research Hospital, Milan, Italy
    For correspondence
    Alberto.Mantovani@humanitasresearch.it
    Competing interests
    The authors declare that no competing interests exist.

Funding

Fondazione Cariplo (Contract n{degree sign} 2015-0564)

  • Rémi Porte

Fondazione AIRC per la ricerca sul cancro ETS (grant IG-2019 Contract n{degree sign} 23465 and 5x1000 Contract n{degree sign} 21147)

  • Rémi Porte

HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA-ESA-ITN,grant number 676129)

  • Alberto Mantovani

Fundação para a Ciência e a Tecnologia (PD/BD/114138/2016)

  • Rita Silva-Gomes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Procedures involving animals handling and care were conformed to protocols approved by the Humanitas Clinical and Research Center (Rozzano, Milan, Italy) in compliance with national (4D.L. N.116, G.U., suppl. 40, 18-2-1992 and N. 26, G.U. march 4, 2014) and international law and policies (European Economic Community Council Directive 2010/63/EU, OJ L 276/33, 22.09.2010; National Institutes of Health Guide for the Care and Use of Laboratory Animals, U.S. National Research Council, 2011). All efforts were made to minimize the number of animals used and their suffering. The study was approved by the Italian Ministry of Health (742/2016-PR).

Human subjects: DNA was obtained from 57 pediatric patients with invasive pulmonary disease (IPD) and 521 age- and sex-matched healthy controls from the cohort described by Garcia-Laorden and collaborators (García-Laorden et al., 2020). DNA samples were provided by Carlos Rodriguez-Gallego, Ignacio Obando and Elena Colino .

Reviewing Editor

  1. Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece

Version history

  1. Received: March 13, 2022
  2. Preprint posted: April 15, 2022 (view preprint)
  3. Accepted: May 23, 2023
  4. Accepted Manuscript published: May 24, 2023 (version 1)
  5. Version of Record published: June 14, 2023 (version 2)

Copyright

© 2023, Porte et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 481
    Page views
  • 82
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rémi Porte
  2. Rita Silva-Gomes
  3. Charlotte Theroude
  4. Raffaella Parente
  5. Fatemeh Asgari
  6. Marina Sironi
  7. Fabio Pasqualini
  8. Sonia Valentino
  9. Rosanna Asselta
  10. Camilla Recordati
  11. Marta Noemi Monari
  12. Andrea Doni
  13. Antonio Inforzato
  14. Carlos Rodriguez-Gallego
  15. Ignacio Obando
  16. Elena Colino
  17. Barbara Bottazzi
  18. Alberto Mantovani
(2023)
Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
eLife 12:e78601.
https://doi.org/10.7554/eLife.78601

Further reading

    1. Immunology and Inflammation
    Atomu Yamaguchi, Noriaki Maeshige ... Hidemi Fujino
    Research Article

    The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Huiyun Lyu, Guohua Yuan ... Yan Shi
    Research Article

    Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.