Induction of Pulmonary Granuloma Formation by Propionibacterium acnes Is Regulated by MyD88 and Nox2.
Sarcoidosis is characterized by noncaseating granulomas with an unknown cause that present primarily in the lung. Propionibacterium acnes, an immunogenic commensal skin bacterium involved in acne vulgaris, has been implicated as a possible causative agent of sarcoidosis. Here, we demonstrate that a viable strain of P. acnes isolated from a patient with sarcoidosis and instilled intratracheally into wild-type mice can generate pulmonary granulomas similar to those observed in patients with sarcoidosis. The formation of these granulomas is dependent on the administration of viable P. acnes. We also found that mice deficient in the innate immunity adapter protein MyD88 had a greater number and a larger area of granuloma lesions compared with wild-type mice administered P. acnes. Early after P. acnes administration, wild-type mice produced proinflammatory mediators and recruited neutrophils into the lung, a response that is dependent on MyD88. In addition, there was an increase in granuloma number and size after instillation with P. acnes in mice deficient in CybB, a critical component of nicotinamide adenine dinucleotide phosphate oxidase required for the production of reactive oxygen species in the phagosome. Myd88-/-or Cybb-/-mice both had increased persistence of P. acnes in the lung, together with enhanced granuloma formation. In conclusion, we have generated a mouse model of early granuloma formation induced by a clinically relevant strain of P. acnes isolated from a patient with sarcoidosis, and, using this model, we have shown that a deficiency in MyD88 or CybB is associated with impaired bacterial clearance and increased granuloma formation in the lung.
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Jessica L
JL
Werner
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Sylvia G
SG
Escolero
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Jeff T
JT
Hewlett
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Tim N
TN
Mak
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Brian P
BP
Williams
2 Department of Human Pathology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Yoshinobu
Y
Eishi
1 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and.
Gabriel
G
Núñez
D000818:Animals; D004195:Disease Models, Animal; D006099:Granuloma / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000382:microbiology* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011425:Propionibacterium acnes / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017565:Sarcoidosis, Pulmonary / Q000382:microbiology / Q000473:pathology; D014132:Trachea / Q000382:microbiology
D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
Propionibacterium acnes; granulomas; sarcoidosis