Arginase 1 activity worsens lung‐protective immunity against Streptococcus pneumoniae infection

Abstract

Type 2 helper cell (Th2) dominated chronic lung diseases such as asthma are characterized by an increased risk for bacterial lung infections. However, the underlying mechanisms are poorly defined. Arginase 1 (Arg1) 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. Here we examined the effect of Th2 cytokine induced upregulation or lung myeloid cell specific conditional knockdown of Arg1 on lung resistance against Streptococcus pneumoniae (Spn) in mice. Lung macrophages responded with a profound induction of Arg1 mRNA and protein to treatment with IL-13 both in vitro and in vivo. IL-13-induced Arg1 activity in the lungs of mice led to significantly attenuated lung-protective immunity against Spn, while conditional Arg1 knockdown had no effect on lung-protective immunity against Spn. Collectively, the data show that Th2 cytokine induced increased Arg1 activity worsens lung-protective immunity against Spn, and interventions to block Th2 cytokine induced lung Arg1 activity may thus be a novel immunomodulatory strategy to lower the risk of bacterial infections in asthmatic patients. Keywords:Alternative macrophage activation r Arg1 r IL-13 r Inflammation r Lung Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergic asthma is a chronic inflammatory disease of the central and peripheral airways characterized by allergen-induced, immunoglobulin (Ig) E mediated early and late bronchial obstruction, chronic airway inflammation, and airway hyperresponsiveness (AHR), eventually leading to large and small airway remodeling [1,2]. Previous studies have implicated type 2 helper cell (Th2) cytokines including IL-4, IL-5, and IL-13 released by various leukocyte subsets such as eosinophils, mast cells, lymphocytes, as well as basophils and macrophages in the pathogenesis of allergic asthma [1,3].Correspondence: Prof. Ulrich A. Maus e-mail: Maus. Ulrich@mh-hannover.de More recent studies in asthmatic patients and animal models of allergic asthma have identified arginase 1 (Arg1) as a key player in the pathophysiology of this disease [3][4][5]. Arg1 is a cytosolic enzyme that hydrolyzes L-arginine to L-ornithine and urea and is constitutively expressed in the liver as a component of the urea cycle [6]. In the so-called classically activated macrophages, particularly Th1 cytokines such as TNF-α together with IFN-γ and IL-12 as well as inducible NO synthase (iNOS, NOS2), which produces antimicrobial NO as part of the innate immune response to bacterial infections, shape their activation profile [7]. In response to Th2 cytokines however, alveolar macrophages are polarized toward a state of alternative activation, which may be achieved in * These authors are co-first authors.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1716-1726 Immunity ...

Arginase-1 Expression in Myeloid Cells Regulates Staphylococcus aureus Planktonic but Not Biofilm Infection

“…Although MDSC depletion improved biofilm clearance by enhancing monocyte proinflammatory activity (12,14), the mechanism of action and whether Arg-1 was involved remained unclear. This was an important issue to address, since Arg-1 activity has been implicated in several types of cancers, Alzheimer's disease, and infection (18,24,35,36). In the current study, we used two mouse models of device-associated S. aureus biofilm infection to determine the role of myeloid-derived Arg-1 in shaping leukocyte infiltrates and promoting biofilm persistence.…”

“…However, the effects of MDSC Arg-1 on inhibition of T cell proliferation may be context dependent, as some studies have not demonstrated a role for the enzyme (33,34). Previous work reported that myeloid-derived Arg-1 expression has a pathological role in several cancers, Alzheimer's disease, and bacterial and helminth infections, establishing it as a key enzyme in dictating disease pathogenesis and immune outcomes (18,24,35,36). Therefore, elevated Arg-1 expression by MDSCs and/or macrophages may participate in preventing an effective immune response to S. aureus biofilm infection through the depletion of extracellular arginine and suppression of proinflammatory responses.…”

Dual role of arginine metabolism in establishing pathogenesis

“…Apart from intracellular bacteria, extracellular bacteria like Streptococcus pneumonia also modulate host arginase. S. pneumonia infection of alveolar macrophages induces arginase I expression in an IL-13-dependent manner, resulting in attenuated host defense against this pathogen during lung infection [31]. Similarly, Pseudomonas -infected lungs demonstrate a ~10-fold increase in arginase activity and a decrease in iNOS activity, leading to decreased production of NO [29].…”

Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

“…IL-5 and IL-13 are potent inducers of eosinophil chemotaxis in the lung (Pope et al, 2001) and IL-13 has been shown to be involved with M2 macrophage polarization causing depressed antibacterial immunity (Knippenberg et al, 2015). Therefore, we next studied these two innate type 2 effector cells.…”

“…Moreover, IL-13 induced M2 macrophages can cause reduced antibacterial immunity (Knippenberg et al, 2015). Recent data also suggest that development of acute exacerbations of infection is not caused by the acquisition of new strains but rather a clonal expansion of existing strains Stenbit and Flume, 2011).…”