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Cell Line-Specific Estrogen Responses Uncover Functional Sex Differences in Murine Macrophages
Alison M Veintimilla1, Zoe Turner1, Nana Owusu-Boaitey1
1University of Maryland College Park.
Research Square
|July 9, 2025
Summary
Immune cell responses to estrogen differ based on cell origin and environment. Sex-aware approaches are crucial for accurate immunological research and understanding disease outcomes.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Macrophages are key immune cells influenced by gonadal hormones, yet their responses to hormones are poorly understood.
- Estrogen impacts immune cell function and contributes to sex differences in disease.
- RAW 264.7 (male-derived) and J774A.1 (female-derived) macrophages are common research models but their sex-specific responses are unclear.
Purpose of the Study:
- To investigate estrogen receptor (ER) expression and functional responses to 17β-estradiol (E2) in male-derived RAW 264.7 and female-derived J774A.1 macrophages.
- To evaluate macrophage behavior in 2D culture and within a 3D hydrogel system under sex-matched and sex-mismatched media conditions.
- To highlight the necessity of sex-aware methodologies in immunological studies.
Main Methods:
- Macrophages were treated with varying concentrations of 17β-estradiol (E2) and analyzed for viability, ER expression, phenotype, MMP9 levels, and phagocytosis.
- Macrophages were cultured in sex-specific conditioned media within a 3D hydrogel system.
- Proliferation and MMP9 production were assessed in encapsulated cells exposed to sex-matched or sex-mismatched media.
Main Results:
- Distinct differences were observed in ER expression and macrophage functions (proliferation, inflammation, matrix remodeling, phenotype skewing) between male-derived and female-derived cell lines.
- The hormonal environment significantly affected macrophage behavior in the 3D hydrogel system.
- Female-derived macrophages showed increased proliferation sensitivity to sex-mismatched environments, while male-derived macrophages exhibited altered enzyme activity with female-conditioned media.
Conclusions:
- Macrophage behavior is influenced by both their sex-derived origin and the surrounding hormonal and environmental context.
- Experimental models must account for these sex-specific differences to accurately reflect immune responses and disease pathogenesis.
- Sex-aware approaches are essential for advancing immunological research and understanding sex disparities in health and disease.
