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17?-estradiol protects females against influenza by recruiting neutrophils and
increasing virus-specific CD8 T cell responses in the lungs
#MMPMID24522912
Robinson DP
; Hall OJ
; Nilles TL
; Bream JH
; Klein SL
J Virol
2014[May]; 88
(9
): 4711-20
PMID24522912
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17?-Estradiol (E2) treatment limits the pathology associated with pulmonary
diseases caused by pathogens, allergens, and asthma, partly by reducing the
production of proinflammatory cytokines and chemokines. To test the hypothesis
that E2 protects against influenza A virus (IAV) infection by altering the
recruitment and activity of innate immune cells and T cells, chemokine
concentrations were measured and innate and adaptive immune cells were enumerated
from the lungs of E2- and placebo-treated ovariectomized female C57BL/6 mice
following infection. Females treated with E2 experienced less morbidity but had
similar lung virus titers to placebo-treated females. Females treated with E2 had
lower induction of CCL2 but higher CCL3 and CXCL1 responses in their lungs than
placebo-treated females. Pulmonary recruitment of neutrophils, NK cells,
macrophages, and dendritic cells was increased following infection, but only
neutrophil numbers were greater in E2-treated than placebo-treated females.
Neutrophils enhance the responses of influenza virus-specific CD8 T cells to
promote virus clearance and improve the outcome of infection. Total numbers of
virus-specific CD8 T cells were not altered by treatment with E2, but the
proportion of gamma interferon (IFN-?)- and tumor necrosis factor alpha
(TNF-?)-producing, virus-specific CD8 T cells was increased. Neutrophil depletion
in E2-treated females increased morbidity, reduced pulmonary production of
chemoattractants for neutrophils, and reduced IFN-? production by virus-specific
CD8 T cells. Neutrophils mediate both inflammation and tissue repair during IAV
infection and are regulated by E2 to improve the outcome of influenza in females.
IMPORTANCE: Severe influenza is associated with excessive inflammation that leads
to tissue damage. We demonstrate that estradiol (E2) is a potent
anti-inflammatory hormone that reduces the severity of influenza A virus
infection in females. Treatment of female C57BL/6 mice with E2 does not affect
virus replication but rather alters the production of chemokines, pulmonary
recruitment of neutrophils, and the cytokine responses of virus-specific CD8 T
cells to protect females against severe influenza.
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