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* Istituto Clinico Humanitas, Rozzano (Milan), Italy;
Institute of General Pathology, University of Milan, Italy;
Institut National de la Santé et de la Recherche Médicale U564 and Laboratoire de Immunologie et Allergologie, University Hospital of Angers, Angers, France;
Centre de Immunologie Pierre Fabre, Saint Julien Genevois, France; and
¶ Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
The long pentraxin PTX3 is a fluid-phase pattern recognition receptor, which plays a nonredundant role in resistance against selected pathogens. PTX3 has properties similar to Abs; its production is induced by pathogen recognition, it recognizes microbial moieties, activates complement, and facilitates cellular recognition by phagocytes. The mechanisms responsible for the effector function of PTX3 in vivo have not been elucidated. OmpA, a major outer membrane protein of Gram-negative Enterobacteriaceae, is a microbial moiety recognized by PTX3. In the air pouch model, KpOmpA induces an inflammatory response, which is amplified by coadministration of PTX3 in terms of leukocyte recruitment and proinflammatory cytokine production. PTX3 did not affect the inflammatory response to LPS, a microbial moiety not recognized by PTX3. As PTX3 binds to C1q and modulates the activation of the complement cascade, we assessed the involvement of complement in the amplification of the response elicited by KpOmpA and PTX3. Experiments performed using cobra venom factor, C1-esterase inhibitor, and soluble complement receptor 1 indicate that PTX3 amplifies the inflammatory response to KpOmpA through complement activation. The results reported here demonstrate that PTX3 activates a complement-dependent humoral amplification loop of the innate response to a microbial ligand.
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1 This work was supported by Associazione Italiana per la Ricerca sul Cancro, Ministero Istruzione Università e Ricerca, European Commission (MUGEN, EMBIC, FLUINNATE), Fondazione CARIPLO (Project NOBEL), and Telethon (GGP05095).
2 A.C., and V.M., equally contributed to this paper.
3 Address correspondence and reprint requests to Dr. Alberto Mantovani, Istituto Clinico Humanitas, Via Manzoni 56, Rozzano, Italy. E-mail address: alberto. mantovani{at}humanitas.it
4 Abbreviations used in this paper: PRR, pattern recognition receptor; OmpA, outer membrane protein A; KpOmpA, Klebsiella pneumoniae OmpA; C1-INH, C1 esterase inhibitor; sCR1, soluble complement receptor 1; CVF, cobra venom factor.
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  V. Maina, A. Cotena, A. Doni, M. Nebuloni, F. Pasqualini, C. M. Milner, A. J. Day, A. Mantovani, and C. Garlanda Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6 J. Leukoc. Biol., July 1, 2009; 86(1): 123 - 132. [Abstract] [Full Text] [PDF]
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