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Regulation of leukocyte recruitment by the long pentraxin PTX3

Nature Immunology volume 11, pages 328–334 (2010)Cite this article

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Abstract

Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.

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Figure 1: Interaction of PTX3 with P-selectin.
Figure 2: Binding site for P-selectin on PTX3.
Figure 3: The role of the PTX3 glycosidic moiety in the PTX3–P-selectin interaction.
Figure 4: PTX3 binds P-selectin in a cell-based context.
Figure 5: PTX3 inhibits rolling interactions in vivo.
Figure 6: Exogenous PTX3 dampens early leukocyte recruitment in vivo.
Figure 7: Role of endogenous PTX3 in leukocyte recruitment.
Figure 8: PTX3 dampens PMN recruitment in a model of acid-induced acute lung injury.

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Acknowledgements

We thank D. Vestweber (Max Planck Institute for Molecular Biomedicine) for blocking monoclonal antibody to mouse P-selectin (Rb40.34); M. Locati (Istituto Clinico Humanitas, Rozzano, and University of Milan) for CHO cells transfected with the chemokine decoy receptor D6; G. Kansas (Northwestern University) for P-selectin-transfected CHO cells. F. Fumagalli (Istituto di Ricerche Farmacologiche Mario Negri) and M. Amigoni (University of Milano-Bicocca) for support in acute lung injury experiments; M. Stravalaci for assistance; and members of the Laboratory for Immunology and Inflammation for advice and discussions. Supported by the European Commission (HEALTH-F4-2008-202156 TOLERAGE), the European Research Council (project HIIS), Telethon (GGP05095), the Cassa di Risparmio delle Provincie Lombarde Foundation (NOBEL project), Ministero Università e Ricerca (MIUR–FIRBRBLA039LSF), the University of Milan (FIRST project), the Fondazione Humanitas per la Ricerca and Italian Association for Cancer Research, the International Graduate School in Molecular Medicine (Vita-Salute San Raffaele University, Italy; L.D.), the European Molecular Biology Organization (ASTF 293-2008 to L.D.), the National Institutes of Health (HL080166 to V.E.), the Fondazione Cariverona, Italian Ministry of Education and Research (G.C.), Fondazione Italiana Sclerosi Multipla, Genova, Italy (G.C.) and the National Multiple Sclerosis Society (G.C.).

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Authors and Affiliations

  1. Laboratory for Immunology and Inflammation, Instituto di Ricovero e Cura a Carattere Scientifico–Istituto Clinico Humanitas, Rozzano, Italy

    Livija Deban, Remo Castro Russo, Marina Sironi, Federica Moalli, Ivan Cuccovillo, Sonia Valentino, Andrea Doni, Cecilia Garlanda, Silvio Danese, Barbara Bottazzi & Alberto Mantovani

  2. Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Remo Castro Russo

  3. Mario Negri Institute, Milan, Italy

    Vanessa Zambelli, Antonio Bastone & Marco Gobbi

  4. Department of Experimental Medicine, University of Milano-Bicocca, Milan, Italy

    Margherita Scanziani & Vanessa Zambelli

  5. Sigma-Tau Research and Development, Pomezia, Italy

    Giovanni Salvatori

  6. Tecnogen, Ricerca e Sviluppo, Piana di Monte Verna, Italy

    Marica Sassano

  7. Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy

    Virgilio Evangelista

  8. Department of Pathology, University of Verona, Verona, Italy

    Barbara Rossi, Elena Zenaro, Gabriela Constantin & Carlo Laudanna

  9. Dipartimento di Medicina Traslazionale, University of Milan, Milan, Italy

    Alberto Mantovani

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Contributions

L.D., B.B. and A.M. planned the research, analyzed and interpreted data and wrote the manuscript; L.D., R.C.R., M.Sironi., F.M., M.Scanziani and V.Z. did the animal experiments; A.B. and M.G. did the SPR experiments; C.L. did and analyzed leukocyte rolling experiments; S.V. and I.C. participated in purification of recombinant proteins and helped with mouse breeding and genotyping; L.D. and A.D. did and analyzed flow cytometry and microtiter plate binding assays; G.S. generated deglycosylated PTX3 by enzymatic digestion; M.Sassano. generated deglycosylated PTX3 by site-directed mutagenesis; G.C., B.R. and E.Z. did and analyzed the intravital microscopy experiments; and C.G., V.E. and S.D. contributed to data analysis and interpretation.

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Correspondence to Alberto Mantovani.

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Deban, L., Russo, R., Sironi, M. et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 11, 328–334 (2010). https://doi.org/10.1038/ni.1854

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