Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response.
Pentraxins are a superfamily of conserved proteins that are characterized by a cyclic multimeric structure. The classical short pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP), are acute-phase proteins produced in the liver in response to inflammatory mediators. Short pentraxins regulate innate resistance to microbes and the scavenging of cellular debris and extracellular matrix components. In contrast, long pentraxins have an unrelated, long amino-terminal domain coupled to the carboxy-terminal pentraxin domain, and differ, with respect to short pentraxins, in their gene organization, chromosomal localization, cellular source, and in their stimuli-inducing and ligand-recognition ability. To investigate the in vivo function of the long pentraxin PTX3, we generated mice deficient in Ptx3 by homologous recombination. Ptx3-null mice were susceptible to invasive pulmonary aspergillosis. Ptx3 binds selected microbial agents, including conidia of Aspergillus fumigatus, and we found that susceptibility of Ptx3-null mice was associated with defective recognition of conidia by alveolar macrophages and dendritic cells, as well as inappropriate induction of an adaptive type 2 response. Thus, the long pentraxin Ptx3 is a secreted pattern-recognition receptor that has a non-redundant role in resistance to selected microbial agents, in particular to the opportunistic fungal pathogen Aspergillus fumigatus.
Garlanda
Cecilia
C
Department of Immunology and Cell Biology, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy.
Hirsch
Emilio
E
Bozza
Silvia
S
Salustri
Antonietta
A
De Acetis
Marika
M
Nota
Rachele
R
Maccagno
Alessia
A
Riva
Federica
F
Bottazzi
Barbara
B
Peri
Giuseppe
G
Doni
Andrea
A
Vago
Luca
L
Botto
Marina
M
De Santis
Rita
R
Carminati
Paolo
P
Siracusa
Gregorio
G
Altruda
Fiorella
F
Vecchi
Annunciata
A
Romani
Luigina
L
Mantovani
Alberto
A
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism*; D001228:Aspergillosis / Q000235:genetics / Q000382:microbiology* / Q000473:pathology; D001232:Aspergillus fumigatus / Q000254:growth & development / Q000378:metabolism*; D001921:Brain / Q000382:microbiology; D002097:C-Reactive Protein / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D017353:Gene Deletion; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D011995:Recombination, Genetic; D000683:Serum Amyloid P-Component / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D018418:Th2 Cells / Q000276:immunology; D000099153:Pentraxins
D000935:Antifungal Agents; D002097:C-Reactive Protein; D016207:Cytokines; D000683:Serum Amyloid P-Component; D000099153:Pentraxins