Role of arginase 1 in lung protective immunity against Streptococcus pneumoniae in mice

Abstract

Type 2 helper cell (TH2) dominated chronic lung diseases like asthma are associated with an increased risk for bacterial lung infections. However, the underlying mechanisms are poorly defined. Arginase 1 has been suggested to play an important role in the pathophysiology of asthma, and is rapidly induced in lung macrophages by TH2 cytokines, thereby limiting macrophage-derived antimicrobial nitric oxide (NO) production. However, the interplay between TH2 cytokine-dependent upregulation of Arg1 and its effect on lung protective immunity against bacterial infection has not been examined in detail. We here examined the effect of TH2 cytokine-induced upregulation or conditional knockdown of Arg1 in macrophages on lung resistance against Streptococcus pneumoniae. Lung macrophages responded with a profound and specific induction of Arg1 mRNA and protein to treatment with TH2 cytokines both in vivo and in vitro. Increased Arg1 activity was accompanied by both significantly attenuated lung protective immunity in mice challenged with S. pneumoniae and attenuated macrophage killing of S. pneumoniae in vitro. In contrast, conditional knock-down of Arg1 in lung macrophages did not impair lung protective immunity against S. pneumoniae, relative to S. pneumoniae-infected WT mice. Collectively, the data show that TH2 cytokine dependent increased but not decreased Arg1 activity worsens lung protective immunity against major lung-tropic pathogens such as S. pneumoniae. Interventions to limit Arg1 activity in the lung might be a novel immunomodulatory strategy for asthmatic patients to cope with bacterial lung infections.