Abstract
Lung diseases characterized by type 2 inflammation are reported to occur with a female bias in prevalence/severity in both humans and mice. This includes previous work examining multi-walled carbon nanotube (MWCNT)-induced eosinophilic inflammation, in which a more exaggerated M2a phenotype was observed in female alveolar macrophages (AMs) compared to males. The mechanisms responsible for this sex difference in AM phenotype are still unclear, but estrogen receptor (ER) signaling is a likely contributor. Accordingly, male AMs downregulated ERα expression after MWCNT exposure while female AMs did not. Thus, ER antagonist Fulvestrant was administered prior to MWCNT instillation. In females, Fulvestrant significantly attenuated MWCNT-induced M2a gene expression and eosinophilia without affecting IL-33. In males, Fulvestrant did not affect eosinophil recruitment but reduced IL-33 and M2a genes compared to controls. Regulation of cholesterol efflux and oxysterol synthesis is a potential mechanism through which estrogen promotes the M2a phenotype. Levels of oxysterols 25-OHC and 7α,25-OHC were higher in the airways of MWCNT-exposed males compared to MWCNT-females, which corresponds with the lower IL-1β production and greater macrophage recruitment previously observed in males. Sex-based changes in cholesterol efflux transporters Abca1 and Abcg1 were also observed after MWCNT exposure with or without Fulvestrant. In vitro culture with estrogen decreased cellular cholesterol and increased the M2a response in female AMs, but did not affect cholesterol content in male AMs and reduced M2a polarization. These results reveal the modulation of (oxy)sterols as a potential mechanism through which estrogen signaling may regulate AM phenotype resulting in sex differences in downstream respiratory inflammation.
| Original language | English |
|---|---|
| Article number | e23350 |
| Pages (from-to) | e23350 |
| Journal | FASEB Journal |
| Volume | 38 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2024 |
Funding
This work was supported by grants received from the National Institutes of Environmental Health Sciences R21ES030978‐01 (A. Holian) and R01ES028829 (K. Gowdy). K. Ronacher is supported by the Australian National Health and Medical Research Council (2019167) and the Mater Foundation. The Fluorescence Cytometry Core and Inhalation and Pulmonary Physiology Core at the University of Montana are supported by National Institutes of General Medical Sciences grant P30GM103338 and the BD FACSAria Fusion™ Flow Cytometer and Cell Sorter provided by the National Institutes of Health S10‐OD025019. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Dr. Nigel Walker and the National Toxicology Program of the National Institute of Environmental Health Sciences for providing the MWCNTs and the Research Triangle Institute for the characterization of the MWCNTs. We also thank Dr. Suzanne Wardell (Duke University School of Medicine, Durham, NC, USA) for their expert advice on executing and troubleshooting the Fulvestrant studies presented throughout this manuscript.
| Funder number |
|---|
| R01ES028829 |
| S10‐OD025019 |
| P30GM103338 |
| 2019167 |
Keywords
- Fulvestrant
- carbon nanotubes
- cholesterol
- estrogen
- inflammation
- lung
- macrophage
- oxysterol
- respiratory
- sex
- Lung/metabolism
- Inflammation/chemically induced
- Humans
- Macrophages/metabolism
- Cholesterol/metabolism
- Mice, Inbred C57BL
- Interleukin-33/metabolism
- Male
- Sex Characteristics
- Nanotubes, Carbon/toxicity
- Animals
- Female
- Mice