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(American Journal of Pathology. 2004;164:1915-1924.)
© 2004 American Society for Investigative Pathology

Estrogen Receptor-1 (Esr1) and -2 (Esr2) Regulate the Severity of Clinical Experimental Allergic Encephalomyelitis in Male Mice

Magdalena Polanczyk^*, Srikanth Yellayi, Alex Zamora^*, Sandhya Subramanian^*, Micah Tovey^*, Arthur A. Vandenbark^*, Halina Offner^*, James F. Zachary, Parley D. Fillmore, Elizabeth P. Blankenhorn, Jan-Åke Gustafsson^¶ and Cory Teuscher^||

From the Department of Neurology,^*Oregon Health and Science University, Portland, Oregon; the Department of Pathobiology,University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Pathobiology,University of Illinois at Urbana-Champaign, Urbana, Illinois; the Department of Microbiology and Immunology,Drexel University College of Medicine, Philadelphia, Pennsylvania; the Department of Medicine,||University of Vermont, Burlington, Vermont; and the Department of Medical Nutrition,^¶Karolinska Institute, Stockholm, Sweden

Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 () gene (Esr1^–/–) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1^+/– or wild-type (Esr1^+/+) controls when immunized with myelin basic protein peptide Ac1-11 (MBP_Ac1-11). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (ß) gene (Esr2^–/–) does not differ from that of wild-type (Esr2^+/+) mice. However, Esr2^+/– mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBP_Ac1-11-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBP_Ac1-11-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon- secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor- secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2^+/– mice. Wild-type Esr2^+/– mice exhibited EAE equivalent in severity to that seen in Esr2^+/– Esr2^+/– control constructs; both of which were more severe than the clinical signs observed in Esr2^+/– wild-type and wild-type wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.

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