Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens

Kasmi, Karim C. El; Qualls, Joseph E.; Pesce, John; Smith, Amber M.; Thompson, Robert W.; Henao-Tamayo, Marcela; Basaraba, Randall J.; König, Till; Schleicher, Ulrike; Koo, Mi-Sun; Kaplan, Gilla; Fitzgerald, Katherine A.; Tuomanen, Elaine; Orme, Ian M.; Kanneganti, Thirumala‐Devi; Bogdan, Christian; Wynn, Thomas A.; Murray, Peter J.

doi:10.1038/ni.1671

Cited by 558 publications

(660 citation statements)

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“…Therefore, our study expands previous reports on conditional Arg1 deletion in a pneumococcal sepsis model [24] by showing that lung myeloid cell specific Arg1 deletion in pneumococcal pneumonia, causing only a minor Arg1 induction in mice, does not affect local lung-protective immunity against this pathogen.…”

Section: Discussionsupporting

confidence: 62%

“…Having found that IL-13-induced Arg1 upregulation impaired lung-protective immunity against Spn, we next questioned what effect conditional Arg1 deficiency in lung myeloid cells (conditional Arg 1 KO, [24]) would have on lung-protective immunity against Spn infection. After infection with Spn, Arg1 KO mice demonstrated a significantly reduced Arg1 protein expression ( Fig.…”

Section: Effect Of Myeloid-specific Conditional Ko Of Arg1 On Lung-prmentioning

confidence: 99%

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

et al. 2015

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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 ...

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Section: Discussionsupporting

confidence: 62%

Section: Effect Of Myeloid-specific Conditional Ko Of Arg1 On Lung-prmentioning

confidence: 99%

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

et al. 2015

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“…adapting their genetic program for protection against NO (37), iNOS exclusion from the phagosome (38), and macrophage arginase 1 induction (39). Despite phagocytosis and high iNOS levels, skin inMDSCs were unable to kill BCG or the fast-growing M. smegmatis, showing that mycobacteria were also able to escape the hostile NO environment in inMDSCs.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium bovis Bacillus Calmette-Guérin Vaccination Mobilizes Innate Myeloid-Derived Suppressor Cells Restraining In Vivo T Cell Priming via IL-1R–Dependent Nitric Oxide Production

Martino

Badell

Abadie

et al. 2010

The Journal of Immunology

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“…In our model of nonlethal influenza infection, we observed the highest levels of iNOS and IL-6, but also Arg I and IL-10, in subpopulation Mv. Arg I suppresses NO production through competition for arginine substrate with iNOS (36), and its simultaneous upregulation may help regulate NO levels to prevent NO-mediated pneumonitis and mortality after influenza infection (37). IL-10 deactivates MF proinflammatory cytokine production in vitro (38).…”

Section: Discussionmentioning

confidence: 99%

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

Duan

Vlahos

et al. 2012

The Journal of Immunology

116

119

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Although great progress has been made in delineating lung dendritic cell and lymphocyte subpopulations, similar advances in lung macrophages (MΦs) have been hampered by their intrinsic autofluorescence, cell plasticity, and the complexities of monocyte–MΦ compartmentalization. Using spectral scanning, we define alveolar MΦ autofluorescence characteristics, which has allowed us to develop an alternative flow cytometry method. Using this methodology, we show that mouse lung MΦs form distinct subpopulations during acute inflammation after challenge with LPS or influenza virus, and in chronic inflammatory lung disease consequent to SHIP-1 deletion. These subpopulations are distinguished by differential Mac-1 and CD11c integrin expression rather than classical M1 or M2 markers, and display differential gene signatures ex vivo. Whereas the resolution of acute inflammation is characterized by restoration to a homogenous population of CD11chighMac-1neg/low MΦs reflective of lung homeostasis, chronic inflammatory lung disease associated with SHIP-1 deficiency is accompanied by an additional subpopulation of CD11chighMac-1pos MΦs that tracks with lung disease in susceptible genetic background SHIP-1−/− animals and disease induction in chimeric mice. These findings may help better understand the roles of MΦ subpopulations in lung homeostasis and disease.

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Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens

Cited by 558 publications

References 49 publications

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

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

Mycobacterium bovis Bacillus Calmette-Guérin Vaccination Mobilizes Innate Myeloid-Derived Suppressor Cells Restraining In Vivo T Cell Priming via IL-1R–Dependent Nitric Oxide Production

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

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