Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening bacterial and fungal infections and hyperinflammation. The susceptibility to aspergillosis in experimental CGD (p47(phox-/-) mice) is associated with the failure to control the inherent inflammatory response to the fungus and to restrict the activation of inflammatory Th17 cells. We assessed whether pentraxin (PTX)3, a member of a family of multimeric pattern-recognition proteins with potent anti-Aspergillus activity, could limit pathogenic inflammation in p47(phox-/-) mice by curbing the IL-23/Th17 inflammatory axis in response to the fungus. We found that the production of PTX3 was delayed in CGD mice in infection but exogenous administration of PTX3 early in infection restored antifungal resistance and restrained the inflammatory response to the fungus. This occurred through down-regulation of IL-23 production by dendritic cells and epithelial cells which resulted in limited expansion of IL-23R+ gammadelta+ T cells producing IL-17A and the emergence of Th1/Treg responses with minimum pathology. Thus, PTX3 could be therapeutically used for the exploitation of NADPH-independent mechanism(s) of antifungal immune protection with limited immunopathology in CGD.
D'Angelo
Carmen
C
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
De Luca
Antonella
A
Zelante
Teresa
T
Bonifazi
Pierluigi
P
Moretti
Silvia
S
Giovannini
Gloria
G
Iannitti
Rossana Giulietta
RG
Zagarella
Silvia
S
Bozza
Silvia
S
Campo
Silvia
S
Salvatori
Giovanni
G
Romani
Luigina
L
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity; D002097:C-Reactive Protein / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000276:immunology*; D015966:Gene Expression Regulation, Fungal / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055732:Pulmonary Aspergillosis / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D000683:Serum Amyloid P-Component / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D000099153:Pentraxins
D000935:Antifungal Agents; D002097:C-Reactive Protein; D018836:Inflammation Mediators; D000683:Serum Amyloid P-Component; D000099153:Pentraxins