Regulation of nitric oxide production in Mycobacterium tuberculosis-infected macrophages

Abstract

 Peroxiredoxin 1 (PRDX1) is an antioxidant that detoxifies hydrogen peroxide and peroxynitrite. Compared with wild-type (WT) mice, Prdx1-deficient (Prdx1^−/−) mice showed increased susceptibility to Mycobacterium tuberculosis (Mtb). Infection with Mtb led to significantly shorter mean postinfection (p. i.) survival in Prdx1^−/− (80.8±10.0 days) than in WT mice (143.4±17.5 days). The numbers of viable Mtb in the lungs at 9 weeks p. i. were 10-fold higher in Prdx1^−/− than in WT lungs. Histological examinations showed auramine-rhodamine-stained Mtb was present predominantly in the alveolar sacs of Prdx1^−/− lungs, but few lesions were observed in WT lungs. IFN-γ-activated Prdx1^−/− bone marrow-derived macrophages (BMDMs) did not kill Mtb effectively. Nitric oxide (NO) production levels were lower, and arginase activity and arginase 1 (Arg1) expression levels were higher in IFN-γ-activated Prdx1^−/− than WT BMDMs after Mtb infection. An arginase inhibitor, N^ω-hydroxy-nor-arginine, restored antimicrobial activity and NO production in IFN-γ-activated Prdx1^−/− BMDMs after Mtb infection. At 9 wk p. i., Arg1 mRNA levels were significantly higher in the lungs of Prdx1^−/− than WT mice. These results suggest that PRDX1 contributes to host defenses against Mtb. PRDX1 positively regulates NO production by suppressing Arg1 expression in macrophages infected with Mtb.