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IL-33 Amplifies the Polarization of Alternatively Activated Macrophages That Contribute to Airway Inflammation¹

Mariola Kurowska-Stolarska,^* Bartosz Stolarski,^* Peter Kewin,^* Grace Murphy,^* Christopher J. Corrigan, Sun Ying, Nick Pitman,^* Ananda Mirchandani,^* Batika Rana,^* Nico van Rooijen, Malcolm Shepherd,^* Charlie McSharry,^* Iain B. McInnes,^* Damo Xu,^*2 and Foo Y. Liew^*2

^*Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology, King’s College London, London, United Kingdom; and Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

Alternatively activated macrophages (AAM) play a crucial role in type 2 immunity. Mice deficient in ST2, a receptor for the latest member of the IL-1 family, IL-33, have impaired type 2 immune responses. We therefore reasoned that IL-33/ST2 signaling may be involved in the differentiation and activation of AAM during airway inflammation. We report here that IL-33 changed the quiescent phenotype of alveolar macrophages toward an AAM phenotype that expressed mannose receptor, IL-4R, and produced high levels of CCL24 and CCL17 in an IL-13-dependent manner during IL-33-induced airway inflammation. Neutralization of AAM-derived CCL24 led to an amelioration of IL-33-induced eosinophilia in the lungs. Moreover, depletion of alveolar macrophages reduced IL-33-induced airway inflammation. Additionally, the attenuated OVA-induced airway inflammation in ST2^–/– mice was associated with a decrease in AAM differentiation. In vitro, IL-33 amplified IL-13-induced polarization of alveolar- and bone marrow-derived macrophage toward an AAM phenotype by increasing the expression of arginase I, Ym1, as well as the production of CCL24 and CCL17. IL-13/IL-4R signaling was crucial for IL-33-driven AAM amplification by inducing the expression of ST2L. Finally, we showed that IL-33 was more abundantly expressed in the lung epithelial cells of asthma patients than those from healthy controls, suggesting that IL-33 may be involved in lung macrophage activation in clinical asthma. Taken together, we demonstrate here that IL-33/ST2 plays a significant role in the amplification of AAM polarization and chemokine production which contribute to innate and Ag-induced airway inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study received financial support from the Medical Research Council UK and the Welcome Trust UK.

² Address correspondence and reprint requests to Dr. Foo Y. Liew and Dr. Damo Xu, Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, U.K. E-mail addresses: f.y.liew{at}clinmed.gla.ac.uk and or D.Xu{at}clinmed.gla.ac.uk

³ Abbreviations used in this paper: AAM, alternatively activated macrophage; BAL, bronchoalveolar lavage; BMM, bone marrow-derived macrophage; i.n., intranasal(ly); iNOS, inducible NO synthase; MR, mannose receptor; qPCR, quantitative PCR; ST2, IL-1 receptor-like 1 molecule; ST2L, membrane-bound ST2; sST2, soluble ST2; WT, wild type.