Androgen and Androgen Receptor as Enhancers of M2 Macrophage Polarization in Allergic Lung Inflammation

被引:98
作者
Becerra-Diaz, Mireya [1 ]
Strickland, Ashley B. [1 ]
Keselman, Aleksander [1 ]
Heller, Nicola M. [1 ,2 ]
机构
[1] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Allergy & Clin Immunol, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
COLONY-STIMULATING FACTOR; AIRWAY INFLAMMATION; ALVEOLAR MACROPHAGES; ASTHMA; TESTOSTERONE; MICE; MECHANISMS; LACKING; MURINE; ACTIVATION;
D O I
10.4049/jimmunol.1800352
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4-stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (AR(flox)LysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.
引用
收藏
页码:2923 / 2933
页数:11
相关论文
共 59 条
[31]   Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling [J].
Lanone, S ;
Zheng, T ;
Zhu, Z ;
Liu, W ;
Lee, CG ;
Ma, B ;
Chen, QS ;
Homer, RJ ;
Wang, JM ;
Rabach, LA ;
Rabach, ME ;
Shipley, JM ;
Shapiro, SD ;
Senior, RM ;
Elias, JA .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (04) :463-474
[32]   Instillation and Fixation Methods Useful in Mouse Lung Cancer Research [J].
Limjunyawong, Nathachit ;
Mock, Jason ;
Mitzner, Wayne .
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2015, (102) :1-9
[33]   Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production [J].
Liva, SM ;
Voskuhl, RR .
JOURNAL OF IMMUNOLOGY, 2001, 167 (04) :2060-2067
[34]   Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis [J].
Maolake, Aerken ;
Izumi, Kouji ;
Shigehara, Kazuyoshi ;
Natsagdorj, Ariunbold ;
Iwamoto, Hiroaki ;
Kadomoto, Suguru ;
Takezawa, Yuta ;
Machioka, Kazuaki ;
Narimoto, Kazutaka ;
Namiki, Mikio ;
Lin, Wen-Jye ;
Wufuer, Guzailinuer ;
Mizokami, Atsushi .
ONCOTARGET, 2017, 8 (06) :9739-9751
[35]   Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis [J].
Marcon, R. ;
Claudino, R. F. ;
Dutra, R. C. ;
Bento, A. F. ;
Schmidt, E. C. ;
Bouzon, Z. L. ;
Sordi, R. ;
Morais, R. L. T. ;
Pesquero, J. B. ;
Calixto, J. B. .
BRITISH JOURNAL OF PHARMACOLOGY, 2013, 168 (02) :389-402
[36]   Androgen receptor expression is greater in macrophages from male than from female donors - A sex difference with implications for atherogenesis [J].
McCrohon, JA ;
Death, AK ;
Nakhla, S ;
Jessup, W ;
Handelsman, DJ ;
Stanley, KK ;
Celermajer, DS .
CIRCULATION, 2000, 101 (03) :224-226
[37]   Female mice are more susceptible to the development of allergic airway inflammation than male mice [J].
Melgert, BN ;
Postma, DS ;
Kuipers, I ;
Geerlings, M ;
Luinge, MA ;
van der Strate, BWA ;
Kerstjens, HAM ;
Timens, W ;
Hylkema, MN .
CLINICAL AND EXPERIMENTAL ALLERGY, 2005, 35 (11) :1496-1503
[38]   High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients [J].
Miyoshi, Yasuhide ;
Uemura, Hiroji ;
Umemoto, Susumu ;
Sakamaki, Kentaro ;
Morita, Satoshi ;
Suzuki, Kazuhiro ;
Shibata, Yasuhiro ;
Masumori, Naoya ;
Ichikawa, Tomohiko ;
Mizokami, Atsushi ;
Sugimura, Yoshiki ;
Nonomura, Norio ;
Sakai, Hideki ;
Honma, Seijiro ;
Harada, Masaoki ;
Kubota, Yoshinobu .
BMC CANCER, 2014, 14
[39]   Macrophages in Allergic Asthma: Fine-Tuning Their Pro- and Anti-Inflammatory Actions for Disease Resolution [J].
Moreira, Ana Paula ;
Hogaboam, Cory M. .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2011, 31 (06) :485-491
[40]   Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes [J].
Moulton, Vaishali R. ;
Holcomb, Dana R. ;
Zajdel, Melissa C. ;
Tsokos, George C. .
MOLECULAR MEDICINE, 2012, 18 (03) :370-378