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

Author:

Porte Rémi12ORCID,Silva-Gomes Rita12,Theroude Charlotte3,Parente Raffaella1,Asgari Fatemeh1,Sironi Marina1,Pasqualini Fabio12,Valentino Sonia1,Asselta Rosanna12,Recordati Camilla45,Monari Marta Noemi1,Doni Andrea1,Inforzato Antonio12,Rodriguez-Gallego Carlos6,Obando Ignacio7ORCID,Colino Elena8,Bottazzi Barbara1ORCID,Mantovani Alberto129

Affiliation:

1. IRCCS Humanitas Research Hospital

2. Department of Biomedical Sciences, Humanitas University

3. Infectious Diseases Service Laboratory, Department of Medicine, Lausanne University Hospital, University Hospital of Lausanne

4. Mouse and Animal Pathology Laboratory, Fondazione Filarete

5. Department of Veterinary Medicine, University of Milan

6. Department of Clinical Sciences, University Fernando Pessoa Canarias

7. Department of Pediatrics, Hospital Universitario Virgen del Rocío

8. Department of Pediatrics, Complejo Hospitalario Universitario Insular Materno Infantil

9. William Harvey Research Institute, Queen Mary University of London

Abstract

Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (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 gene 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.

Funder

Fondazione Cariplo

Fondazione AIRC per la ricerca sul cancro ETS

HORIZON EUROPE Marie Sklodowska-Curie Actions

Fundação para a Ciência e a Tecnologia

Ministry of Health - Italy

Fondazione Beppe and Nuccy Angiolini

Société Académique Vaudoise

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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