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Microglial angiotensin type 2 receptors mediate sex-specific expression of inflammatory cytokines independently of circulating estrogen

Garrido-Gil, Pablo ; Pedrosa, Maria A. ; Garcia-Garrote, Maria LU orcid ; Pequeño-Valtierra, Ana ; Rodríguez-Castro, Jorge ; García-Souto, Daniel ; Rodríguez-Pérez, Ana I. and Labandeira-Garcia, Jose L. (2022) In GLIA 70(12). p.2348-2360
Abstract

There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed... (More)

There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1β and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroids.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AT2 receptor, gender, gonadal hormones, interleukins, neuroinflammation, sex chromosome complement, sex dimorphism
in
GLIA
volume
70
issue
12
pages
2348 - 2360
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85135574347
  • pmid:35943203
ISSN
0894-1491
DOI
10.1002/glia.24255
language
English
LU publication?
no
additional info
Publisher Copyright: © 2022 The Authors. GLIA published by Wiley Periodicals LLC.
id
5ceb8030-d3a4-4219-87d5-e85175ce3345
date added to LUP
2025-01-24 11:50:44
date last changed
2025-07-12 12:48:13
@article{5ceb8030-d3a4-4219-87d5-e85175ce3345,
  abstract     = {{<p>There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1β and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroids.</p>}},
  author       = {{Garrido-Gil, Pablo and Pedrosa, Maria A. and Garcia-Garrote, Maria and Pequeño-Valtierra, Ana and Rodríguez-Castro, Jorge and García-Souto, Daniel and Rodríguez-Pérez, Ana I. and Labandeira-Garcia, Jose L.}},
  issn         = {{0894-1491}},
  keywords     = {{AT2 receptor; gender; gonadal hormones; interleukins; neuroinflammation; sex chromosome complement; sex dimorphism}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2348--2360}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{GLIA}},
  title        = {{Microglial angiotensin type 2 receptors mediate sex-specific expression of inflammatory cytokines independently of circulating estrogen}},
  url          = {{http://dx.doi.org/10.1002/glia.24255}},
  doi          = {{10.1002/glia.24255}},
  volume       = {{70}},
  year         = {{2022}},
}