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iNature
In viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate connexin VISA/MAVS- or MITA/sting-mediated innate antiviral responses
.
However, whether and how innate antiviral responses are regulated by neuronal endocrine function is unclear
.
On January 5, 2023, Shu Hongbing and Hu Mingming of Wuhan University jointly published a report entitled "β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral" online in the journal Cellular & Molecular Immunology (IF=22).
response", which found that viral infections reduced serum levels of the β-adrenergic hormones epinephrine and norepinephrine and cellular levels
of their receptors ADRB1 and ADRB2.
Studies have further shown that increased levels of epinephrine/norepinephrine suppress innate antiviral responses
in an ADRB1-/2-dependent manner.
Mechanistically, epinephrine/norepinephrine stimulates the activation of downstream kinase PKA, catalyzes the phosphorylation of MITA at S241, S243 and T263 sites, inhibits MITA activation, and inhibits the innate immune response
of DNA viruses.
In addition, phosphorylation of VISA by PKA at the T54 site antagonizes the innate immune response
of RNA viruses.
Together, these findings reveal the regulatory mechanism of epinephrine/norepinephrine on innate antiviral responses and provide a possible explanation
for increasing host susceptibility to viral infections in stress- and anxiety-promoting situations.
of defense against viral infection.
Structurally conserved pathogen-associated molecular patterns (PAMPs) in microorganisms are recognized by host pattern-recognition receptors (PRRs), thereby inducing type I interferons (IFNs), pro-inflammatory cytokines, and other downstream effector genes
。 The most important viral PAMPs are viral nucleic acids, including viral DNA and/or RNA
.
During RNA virus infection, cytoplasmic viral RNA is sensed by members of the RIG-I-like receptor (RLR) family, including retinoic acid-induced gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) They are recruited to mitochondria-associated adapter proteins called virus-induced signaling adaptor (VISA, also known as MAVS, IPS-1 and Cardif) to deliver signals
.
VISA is a central platform that activates downstream TAK1-IKKβ and TBK1/IKKε kinases, leading to activation of transcription factors NF-κB and IRF3 and induction of type I IFNs
.
In mammalian cells, the most widely expressed and activated cytoplasmic viral DNA sensor is cGMP-AMP (cGAMP) synthase (cGAS
).
The bonding of DNA to cGAS initiates conformational changes at the active site, catalyzes the synthesis of ATP and GTP into a second messenger, cGAMP, which in turn binds to and activates IRF3-activated endoplasmic reticulum (ER) membrane-associated adaptor protein mediation (MITA, also known as STING).
Activated MITA is transferred from ER to a perinuclear punctate structure
via the ER-Golgi intermediate compartment (ERGIC).
In this process, MITA recruits TBK1 and IRF3, leading to phosphorylation of IRF3 and induction
of type I IFNs.
Type I IFNs further induce the expression of downstream antiviral genes through the JAK-STAT pathway, resulting in innate antiviral responses
.
Stress and anxiety increase a person's vulnerability to viruses, such as several different strains
of respiratory viruses.
However, the mechanisms behind this susceptibility are still poorly
understood.
Under physiological conditions, acute stress or anxiety activates the hypothalamus-pituitary-adrenal cortex (HPA) axis and sympathetic nervous system (SNS), leading to the production of stress hormones, including glucocorticoids, epinephrine, and norepinephrine
.
In recent years, the regulation of adaptive immunity and inflammation by stress hormones has been reported
.
For example, several studies have revealed the inhibitory role
of glucocorticoids in lipopolysaccharides (LPS)-induced inflammatory responses and T helper 1 (Th1) differentiation.
In addition, catecholamines have been shown to inhibit LPS-induced expression of cytokines and chemokines
.
Norepinephrine inhibits IFN-γ and TNFα production in mouse intestinal intraepithelial lymphocytes and macrophages via the receptor ADRB1/2
.
Recently, it has been reported that the ADRB2 signaling pathway downregulates the production of IFN-γ in natural killer (NK) cells of the liver to reduce host resistance to murine cytomegalovirus (MCMV) infection
.
However, it is unclear
whether stress hormones modulate innate antiviral responses.
In this study, the researchers found that the levels of the stress hormones epinephrine and norepinephrine in mice after the virus infection and mRNA levels of their receptor ADRB1/2 were down-regulated
.
In addition, the study found that the epinephrine/norepinephrine-ADRB1/2 axis activates protein kinase A (PKA), which in turn phosphorylates the innate immune signaling adapter MITA or VISA, inhibiting its activity, and ultimately leading to inhibition
of the innate antiviral response.
Figure 1.
Viral infection downregulates epinephrine/norepinephrine and its receptors (Diagram from Cellular & Molecular Immunology) Studies have shown that adrenaline and norepinephrine secreted by the adrenal glands and nerve endings bind to the receptor ADRB1/2 and activate the downstream kinase PKA in the uninfected state
。 PKA phosphorylates the innate immune signaling protein VISA at the T54 site after RNA virus infection and MITA
at the S241, S243, and T263 sites after DNA virus infection.
This phosphorylation reaction inhibits the ability
of VISA or MITA to trigger downstream TBK1 or IRF3 activation of antiviral gene expression.
Further studies have shown that after viral infection, epinephrine and norepinephrine and their receptor levels are significantly reduced, thereby inhibiting the inhibitory
effect of epinephrine and norepinephrine on VISA-/MITA-mediated antiviral innate immune signaling pathways.
How viral infections lead to a decrease in the secretion of epinephrine and norepinephrine and the downregulation of their receptors requires further investigation
in future studies.
Figure 2.
Working model of epinephrine and norepinephrine regulating innate antiviral responses (Image from Cellular & Molecular Immunology) Overall, this study revealed a conserved and shared regulatory mechanism
of humoral epinephrine and norepinephrine on innate antiviral responses.
This mechanism may explain how type I interferons are maintained at basal levels in the uninfected state and provide a checkpoint
for innate antiviral immunity following viral infection.
Regulating this mechanism may help develop new treatments
for infectious and inflammatory diseases.
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