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. Myd882/2 or Cybb 2/2 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.

No abstract

Sarcoidosis is characterized by non-caseating granulomas with an unknown etiology that present primarily in the lung. Propionibacterium acnes, an immunogenic commensal skin bacterium involved in acne vulgaris, has been implicated as a causative agent of sarcoidosis because it has been both detected and cultured from granuloma lesions and lymph nodes of sarcoidosis patients. Here we demonstrate that a strain of P.acnes isolated from a sarcoidosis patient and instilled intratracheally into wild type mice can generate pulmonary granulomas. When mice deficient in the innate immunity adapter protein Myd88 are instilled with P.acnes the number and size of granulomas are increased compared to wild type. Additionally there was an increase in granuloma number and size after instillation with P.acnes in mice deficient in Nox2, a critical component of the phagocyte NAPDH that generates reactive oxygen species for microbial killing within the phagosome. Furthermore mice without Myd88 or Nox2 displayed defective killing of P.acnes in the lung, and wild type mice that were given heat-killed P.acnes produce significantly less granulomas then when given viable P.acnes, suggesting that bacterial killing and/or clearance plays a critical role in the development of pulmonary granulomas. In conclusion viable P.acnes can be used to generate a mouse model of pulmonary sarcoidosis, and Myd88 and Nox2 appear to play a key role in the development of these granulomas.

No abstract

No abstract