Patients over 15 years old requiring hospitalization for asthma are up to three times more likely to be female than male. Women comprised 64% of the asthma-associated deaths in 2009. Mainstay asthma therapies are often ineffective in women. Animal studies recapitulate the human disease: the hallmark features of allergic lung inflammation are worse in female mice compared to male mice and estrogen (E2) worsens lung inflammation. The lungs of both female mice and humans with asthma have greater numbers of alternatively activated (or M2) macrophages, correlating with worse lung function in humans. The broad objective of this proposal is to understand the molecular basis of sex differences in macrophages and their contribution to pathogenesis in allergic lung inflammation.
The Specific Aims are to determine intrinsic sex differences in M2 differentiation in macrophages from male and females and the role of sex hormones (E2, DHT) and their receptors in regulating these differences in vitro and in vivo. Based on our preliminary data, we hypothesize that (i) macrophages from females express characteristic M2 phenotypic genes in response to IL-4 more highly compared to male cells and (ii) that E2 promotes and androgens suppress IL-4-induced M2 differentiation. We will test these hypotheses by defining differences in IL-4 receptor expression, IL-4-activated signal transduction pathways and induction of M2 gene expression in different mouse and human macrophage populations in vitro. We will also determine the effect of E2 and DHT on M2 differentiation, monocyte recruitment and macrophage turnover in the lung in vivo using mouse models of allergic lung inflammation in hormone-treated animals. Understanding these sex differences will help uncover novel targets for therapy in asthmatic women and tailor more effective, personalized therapies for asthma and allergic inflammation based on the sex of the patient.

Public Health Relevance

This research will define sex differences in macrophages following exposure to IL-4 and the role of sex hormones in regulating macrophage biology during allergic inflammation in the lung. This will help our understanding of differences in prevalence, severity and drug responses between the sexes in allergic asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Caler, Elisabet V
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Johns Hopkins University
Schools of Medicine
United States
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Becerra-Díaz, Mireya; Strickland, Ashley B; Keselman, Aleksander et al. (2018) Androgen and Androgen Receptor as Enhancers of M2 Macrophage Polarization in Allergic Lung Inflammation. J Immunol 201:2923-2933
Han, MeiLan K; Arteaga-Solis, Emilio; Blenis, John et al. (2018) Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Am J Respir Crit Care Med 198:850-858
Keselman, Aleksander; Fang, Xi; White, Preston B et al. (2017) Estrogen Signaling Contributes to Sex Differences in Macrophage Polarization during Asthma. J Immunol 199:1573-1583
Becerra-Díaz, Mireya; Wills-Karp, Marsha; Heller, Nicola M (2017) New perspectives on the regulation of type II inflammation in asthma. F1000Res 6:1014
Chang, Che-Feng; Wan, Jieru; Li, Qiang et al. (2017) Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. Neurobiol Dis 103:54-69
Keselman, Aleksander; Heller, Nicola (2015) Estrogen Signaling Modulates Allergic Inflammation and Contributes to Sex Differences in Asthma. Front Immunol 6:568