Herpes simplex virus type 1
inflammasome activation in proinflammatory human macrophages is
dependent on NLRP3, ASC, and caspase-1
- Published: February 26, 2020
- https://doi.org/10.1371/journal.pone.0229570
PLoS One. 2020; 15(2): e0229570.
Published online 2020 Feb 26. doi: 10.1371/journal.pone.0229570
PMCID: PMC7043765
PMID: 32101570
Herpes simplex virus type 1 inflammasome activation in proinflammatory human macrophages is dependent on NLRP3, ASC, and caspase-1
Claude Krummenacher, Editor
Author information Article notes Copyright and License information
The
proinflammatory cytokines interleukin (IL)-1β and IL-18 are products of
activation of the inflammasome, an innate sensing system, and important
in the pathogenesis of herpes simplex virus type 1 (HSV-1). The release
of IL-18 and IL-1β from monocytes/macrophages is critical for
protection from HSV-1 based on animal models of encephalitis and genital
infection, yet if and how HSV-1 activates inflammasomes in human
macrophages is unknown.
To investigate this, we utilized both primary
human monocyte derived macrophages and human monocytic cell lines (THP-1
cells) with various inflammasome components knocked-out. We found that
HSV-1 activates inflammasome signaling in proinflammatory primary human
macrophages, but not in resting macrophages. Additionally, HSV-1
inflammasome activation in THP-1 cells is dependent on
nucleotide-binding domain and leucine-rich repeat-containing receptor 3
(NLRP3), apoptosis-associated speck-like molecule containing a caspase
recruitment domain (ASC), and caspase-1, but not on absent in melanoma 2
(AIM2), or gamma interferon-inducible protein 16 (IFI16). In contrast,
HSV-1 activates non-canonical inflammasome signaling in proinflammatory
macrophages that results in IL-1β, but not IL-18, release that is
independent of NLRP3, ASC, and caspase-1. Ultraviolet irradiation of
HSV-1 enhanced inflammasome activation, demonstrating that viral
replication suppresses inflammasome activation. These results confirm
that HSV-1 is capable of activating the inflammasome in human
macrophages through an NLRP3 dependent process and that the virus has
evolved an NLRP3 specific mechanism to inhibit inflammasome activation
in macrophages.
Introduction
The
ability to quickly recognize and respond to pathogens is essential to
host survival. The first opportunity to do so lies in the innate immune
response. One of the most essential aspects of this response is the
recognition of pathogen associated molecular patterns (PAMPs) on the
invading pathogen by the pattern recognition receptors (PRRs) of host
cells [1].
This interaction leads to a number of molecular and cellular signals
that serve to protect the host on cellular and organism levels. One such
innate signaling system is the formation of inflammasomes, which are
intracellular multi-protein complexes that regulate an inflammatory type
of cell death called pyroptosis as well as the production of mature
forms of the inflammatory cytokines IL-1β and IL-18 [2].
Macrophages and myeloid dendritic cells (mDCs) are the primary
producers of these potent proinflammatory cytokines, which drive type 1
immunity in natural killer cells and T cells [3].
The production of these cytokines requires two steps.
The first step,
sometimes referred to as priming, requires activation of the nuclear
factor κB (NF-κB) pathway through the recognition of a PAMP leading to
synthesis of components of the inflammasome, including pro-IL-1β,
pro-IL-18, and pro-caspase-1. The second step involves PRR activation,
oligomerization, and assembly of the inflammasome. This takes place
through one of multiple receptor or adapter proteins that recognize
various PAMPs or danger-associated molecular patterns (DAMPs). These
include members of the nucleotide-binding domain and leucine-rich
repeat-containing receptors (NLR) family of proteins, absent in melanoma
2 (AIM2), and pyrin. NLRP3 responds to a diverse group of PAMPs and
DAMPs, particularly viral RNA [4–7]. In contrast, AIM2 is activated after binding to cytoplasmic double stranded DNA (dsDNA) [8].
Recognition of an appropriate PAMP or DAMP by one of these adapter
proteins leads to apoptosis-associated speck-like molecule containing a
caspase recruitment domain (ASC) assembly and oligomerization followed
by pro-caspase-1 recruitment to the complex. Pro-caspase-1 autocatalysis
to active caspase-1 allows for cleavage of pro-IL-1β and pro-IL-18 to
their active forms, IL-1β and IL-18, and then secretion into the
extracellular space (reviewed in [2,9,10]).
There are other “non-canonical” sensors and caspases that can lead to
inflammasome cytokine release, but the caspase-1 pathway is thought to
be the most relevant in viral infection [11,12].
A number of viruses are known to activate the inflammasome, including influenza, hepatitis C (HCV), HIV, and herpesviruses [10,13].
Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus
that predominantly infects epithelial cells and neurons, but has broad
cell tropism [14].
Specifically, it can infect macrophages, which are one of the
predominant cell types that infiltrate the eye after corneal infection
and are crucial to the innate immune response to HSV-1 and other viruses
[15–17].
Furthermore, monocyte/macrophage production of IL-1β and IL-18 is
critical to prevent severe HSV disease in encephalitis, keratitis, and
vaginal infection in mouse models [17–20].
Therefore, understanding how HSV-1 activates the inflammasome in these
cells is key to developing a comprehensive view of HSV-1 pathogenesis. A
previous study demonstrated that the HSV-1 viral tegument protein VP22
specifically blocks AIM2 inflammasome activation and signaling in the
THP-1 monocyte/macrophage cell line despite production of IL-1β, leaving
the mechanism of HSV-1 activation of the inflammasome in these cells to
be defined [21,22]. Thus, it remains unclear which adapters are required for HSV-1 induction of inflammasome activation in macrophages.
Here,
we report that HSV-1 activates canonical inflammasome signaling, as
measured by IL-18, in both proinflammatory primary human macrophages and
THP-1 cells. Additionally, this activation requires NLRP3, ASC, and
caspase-1, but not AIM2 or IFI16.
Results
HSV-1 activates the inflammasome in primary human monocyte derived macrophages
HSV-1
is known to activate the inflammasome in THP-1 cells, but the mechanism
is unknown and it has not been studied extensively in primary human
macrophages [21,22].
To determine if HSV-1 is capable of activating the inflammasome in
primary human monocyte derived macrophages (MDMs) we infected resting
macrophages (referred to as M0) with HSV-1 and measured IL-18 in
supernatants 24 hours later. The amount of IL-18 detected in HSV-1
infected M0 macrophages was not different than the amount detected in
mock infected macrophages (Fig 1A).
However, some viruses, such as Dengue virus, require a more
inflammatory macrophage phenotype to induce inflammasome activation [23].
Therefore, we incubated MDMs with IFNγ (referred to as M1) prior to
infection with HSV-1 to induce a more proinflammatory cell [24,25]. Unlike the M0 macrophages, M1 macrophages did produce significant amounts of IL-18 after HSV-1 infection (Fig 1B).
Both M0 and M1 macrophages produced IL-18 after incubation with
nigericin (Ng) and LPS, a potent activator of the NLRP3 inflammasome [26,27] (S1A Fig). Proinflammatory (M1) macrophages are often produced by incubating MDMs with IFNγ and LPS [28,29].
However, we found no difference in the amount of IL-18 produced after
HSV-1 infection by M1s stimulated with IFNγ or IFNγ and LPS (S1B Fig). Therefore, we opted to omit the LPS in subsequent experiments.
While mature forms
of both IL-18 and IL-1β are produced by canonical caspase-1 inflammasome
formation, other caspases are capable of processing IL-18 and IL-1β
(reviewed in [30]).
These “non-canonical” pathways do not require an adapter molecule and
are well described for IL-1β. However, mature IL-18 production is
thought to be restricted to canonical inflammasome formation aside from
very limited circumstances (reviewed in [31,32]).
To determine if the production of IL-18 by macrophages after HSV-1
infection was due to canonical inflammasome activation, M1 MDMs were
treated with VX-765, a caspase-1 specific inhibitor [33–35],
prior to either infection with HSV-1 or treatment with nigericin and
LPS. IL-18 in cell supernatants was reduced to amounts not significantly
different from background in the presence of VX-765, suggesting that
IL-18 production is due to canonical inflammasome activation (Fig 1C).
To ensure that VX-765 was neither toxic to the cells nor
non-specifically interfering with HSV-1 sensing by the macrophages, the
same supernatants were tested for TNFα, which is produced by macrophages
in response to HSV-1 infection [36].
There was no significant difference in the amount of TNFα produced
after HSV-1 infection of macrophages incubated with or without VX-765 (Fig 1D).
Interestingly, when IL-1β was measured from these same supernatants,
treatment with VX-765 did not reduce IL-1β levels to background levels
in the HSV-1 infected macrophages, but did in the Ng+LPS treated
macrophages (Fig 1E).
This suggests that HSV-1 induces IL-1β release by both caspase-1
dependent and independent mechanisms, and that IL-18 is a more specific
marker of canonical inflammasome activation in this system.
To
ensure that the varying amounts of IL-18 observed in these experiments
was not due to changes in the ability of HSV-1 to replicate in
macrophages exposed to IFNγ and/or VX-765, M0 and M1 MDMs (with and
without VX-765) were infected with HSV-1. Culture supernatants were
collected after 24 hours, and plaque forming units (PFU) were determined
using a standard plaque assay. No differences were observed in HSV-1
replication in macrophages exposed to IFNγ or VX-765 (Fig 1F).
These results demonstrate that viral replication alone does not account
for differences in inflammasome activation in primary human
macrophages.
HIV and HCV are capable
of activating the inflammasome in monocytes/macrophages via clathrin
mediated endocytosis without infecting them or binding known viral entry
receptors [13].
To test whether HSV-1 activation of the inflammasome in macrophages
requires entry and infection through known mechanisms, MDMs pretreated
with IFNγ were inoculated with HSV-1 mixed with neutralizing human
monoclonal antibodies directed against the HSV-1 glycoprotein D, which
is required for HSV-1 entry [37].
Both WT antibodies and antibodies unable to bind to Fc receptors (Fc
Silent) were utilized to control for any Fc-mediated entry of virus.
While HSV-1 alone induced robust IL-18 release, this was reduced to
background levels in the presence of neutralizing antibody regardless of
whether the antibody was capable of binding to Fc receptors (Fig 1G).
These data confirm that unlike HCV and HIV, HSV-1 must enter
macrophages via viral glycoprotein and receptor mediated pathways to
induce inflammasome activation.
NLRP3, ASC, and caspase-1 are required for inflammasome activation in response to HSV-1
To
confirm that HSV-1 is capable of activating the inflammasome in a
monocyte/macrophage cell line so that dependence on specific
inflammasome proteins could be assessed, THP-1 cells were primed with
phorbol 12-myristate 13-acetate (PMA) overnight and then infected with
HSV-1. IL-18 was measured in supernatants after 24 hours. As previously
reported [38], THP-1 cells produced IL-18 after infection with HSV-1 (Fig 2A). Autoprocessing of caspase-1 results in release of the large (p20) subunit [39].
Therefore, lysates from THP-1 cells either infected with HSV-1 or mock
infected for 4 hours were probed for this cleavage product. As expected,
the caspase-1 p20 sub
Studies in
keratinocytes and human foreskin fibroblasts (HFF) found roles for
IFI16, NLRP3, and AIM2 in HSV-1 inflammasome activation [40,41].
Yet, monocytes/macrophages produce the majority of inflammasome related
cytokines (IL-18 and IL-1β) in other viral infections and play crucial
roles in preventing the most severe manifestations of HSV infection in
mouse models [13,42].
Therefore, to determine what inflammasome components are required for
HSV-1 induced inflammasome activation in macrophages, we infected THP-1
cells lacking various inflammasome proteins. These cells were
constructed using the CRISPR-Cas9 system and previously used to
determine the requirements for human cytomegalovirus (HCMV) inflammasome
activation in macrophages [43].
The ΔHUMCYC cell-line (WT) was used to control for any off-target
effects of the CRISPR-cas9 system. This line was derived from the same
THP-1 cells, but targeted a human pseudogene (HUMCYCPS3). While
HSV-1 infection of the WT, ΔAIM2, and ΔIFI16 THP-1 cells led to
significant IL-18 production, infection of ΔNLRP3, Δcaspase-1, and ΔASC
cells resulted in levels of IL-18 that were not significantly different
from mock infection (Fig 2D).
The amount of IL-18 produced in response to HSV-1 by the ΔAIM2, and
ΔIFI16 THP-1 cells was not significantly different from WT (S2A Fig).
The combination of nigericin with LPS was used as a positive control.
As expected, IL-18 concentrations in supernatants from cells lacking
NLRP3, ASC, and caspase-1 were not above background after nigericin and
LPS exposure [27].
These results indicate that HSV-1 induced canonical inflammasome
activation and IL-18 production and release in macrophages is dependent
on ASC, caspase-1, and NLRP3, but not on the dsDNA sensors IFI16 or
AIM2. These differences were not due to differing replication capacity
in the different knock-out lines as HSV-1 replicated similarly in each
cell line compared to the WT line (Fig 2B).
UV-irradiated HSV-1 increases inflammasome activation
The HSV-1 tegument protein VP22 blocks activation of the AIM2 inflammasome [22]
and, therefore, it is unsurprising that we failed to find a dependence
on AIM2. However, it is possible that HSV-1 has evolved multiple
mechanisms to alter inflammasome activation. To test this hypothesis, we
cultured M0 and M1 MDMs with HSV-1 or UV irradiated HSV-1 (HSV-1/UV).
Interestingly, HSV-1/UV exposure did lead to IL-18 production in M0
macrophages (Fig 3A).
This result suggests that M0 macrophages are capable of inflammasome
formation in response to HSV-1, but that a viral factor that is produced
during the replication cycle (such as VP22) inhibits this activation.
When added to M1 macrophages, HSV-1/UV led to significantly increased
IL-18 production compared to HSV-1 (Fig 3B).
At four hours post infection, little IL-18 was detectable in
supernatants from M1 macrophages, while at eight hours post infection,
IL-18 was significantly higher in M1 macrophages infected with HSV-1
compared to those infected with HSV-1/UV (Fig 3C).
These data suggest that when macrophages are skewed toward an
inflammatory state with IFNγ, a cellular factor is altered that
counteracts the inhibitory mechanism(s) of the virus in M0 macrophages.
However, replication of the virus does continue to lead to some
downregulation of inflammasome activation in IFNγ-treated macrophages
because HSV-1/UV led to increased IL-18 production versus HSV-1, albeit
not until 24 hours post infection. One explanation for this phenomenon
is that UV-irradiating the virus eliminates sufficient production of
VP22 such that AIM2 is able to sense the viral DNA and trigger
inflammasome formation in M0s. Whereas the replication competent virus
inhibits AIM2 via VP22, the M0s lack additional factor(s) required to
trigger inflammasome signaling in response to HSV-1. After skewing with
IFNγ, HSV-1 infection leads to inflammasome formation through a non-AIM2
dependent mechanism and HSV-1/UV is able to trigger inflammasome
signaling through both AIM2 dependent and non-AIM2 dependent mechanisms.
To determine if HSV-1 replication in macrophages results in inhibition
of any non-AIM2 inflammasome proteins, we tested HSV-1/UV infection of
the THP-1 cells lacking AIM2 and NLRP3 and compared them to WT THP-1
cells. In order to more closely replicate the MDM model with IFNγ
stimulation, in this experiment the cells were stimulated with PMA and
then either infected directly or stimulated with IFNγ for an additional
24hrs and then infected (Fig 4).
Similar to what was seen in the MDM model, the WT, ΔAIM2, and ΔNLRP3
cells treated with PMA alone produced more IL-18 in response to HSV-1/UV
than in response to replication competent HSV-1 (Fig 4A).
Interestingly, after the addition of IFNγ, HSV-1 infection led to
significant IL-18 production in the WT and ΔAIM2 cells, with even
greater IL-18 produced with exposure to HSV-1/UV. Again, the ΔNLRP3
cells did not produce IL-18 in response to HSV-1, but did produce a
modest, but statistically significant, amount of IL-18 after infection
with HSV-1/UV (Fig 4B).
These data confirm our findings in the MDMs that HSV-1 infection of
unstimulated macrophages does not lead to inflammasome activation.
Further, they support the hypothesis that replication competent HSV-1 is
capable of decreasing both AIM2 and NLRP3 dependent inflammasome
activation because UV irradiating the virus led to significant increases
in IL-18 release in both the ΔAIM2 and ΔNLRP3 lines at 24 hours
post-infection. IFI16 has been reported to interact with ASC in response
to HSV-1 infection and Kaposi's sarcoma-associated herpesvirus (KSHV)
in HFF cells early during infection, and the HSV-1 immediate early
protein ICPO is known to downregulate IFI16 [41,44,45].
Therefore, we examined IL-18 production in THP-1 cells at 4 and 8 hours
post-infection with HSV-1. Similar to what was observed at 24 hours
post-infection, HSV-1 infection of the WT, ΔAIM2, and ΔIFI16 THP-1 cells
led to significant IL-18 production. However, infection of ΔNLRP3,
Δcaspase-1, and ΔASC cells resulted in minimal production of IL-18 not
significantly different from mock infection (S2C and S2D Fig).
This indicates that in proinflammatory macrophages, IFI16 and AIM2 are
dispensable for HSV-1 induced inflammasome activation early during
infection. In keeping with previously published reports, IFI16 was not
decreased at 4 hours post infection with HSV-1, but IFI16 was decreased
after 24 hours of infection. HSV-1/UV did not decrease IFI16 expression (S2B Fig).
As observed in the MDM model, infection with HSV-1/UV did not lead to
more robust IL-18 production at these earlier time points, which
supports the hypothesis that HSV-1 has evolved mechanisms that require
de novo viral protein translation to inhibit inflammasome signaling.
Discussion
In
this study, we demonstrate for the first time that HSV-1 induces IL-18
production and activation of inflammasomes in primary human macrophages
stimulated with IFNγ through a caspase-1 dependent process. UV
irradiating the virus prior to infection also leads to IL-18 production
in unstimulated primary macrophages, but replication competent HSV-1
does not result in IL-18 release without pre-treatment with IFNγ.
Furthermore, using THP-1 cell lines, we show that HSV-1 induced
canonical inflammasome activation is dependent on NLRP3, ASC, and
caspase-1. By comparing HSV-1 and HSV-1/UV in these THP-1 cells, we also
provide evidence that HSV-1 is capable of decreasing inflammasome
activation through AIM2 and NLRP3 dependent mechanisms. Unlike IL-18, we
found that macrophages are capable of producing IL-1β in a
non-canonical, NLRP3, ASC, and caspase-1 independent manner in response
to HSV-1
. Finally, activation of the inflammasome in macrophages does
not prevent viral replication as measured by plaque assay on macrophage
culture supernatants 24 hours after infection with HSV-1.
Our
data indicate that a cellular factor is altered in macrophages
stimulated with IFNγ that allows for activation of the inflammasome
after HSV-1 infection. Multiple cellular pathways and metabolic programs
are modulated in macrophages exposed to IFNγ [28,29].
While IFNγ is generally accepted as a proinflammatory stimulus, some
inflammatory pathways, including IL-1β production, can be blunted after
IFNγ stimulation in murine, bone-marrow derived macrophages [46].
While we do not know what factor is altered, it is unlikely that it is
NLRP3 itself because prior studies have demonstrated no significant
increases in NLRP3 expression in macrophages after skewing with IFNγ [24,47].
Although a previous study suggested that HSV-1 infection of primary human macrophages does not lead to inflammasome activation [48], the macrophages in that study were only stimulated with the TLR2 agonist Pam3Cys
and not IFNγ. Our data in M0-like MDMs showing that HSV-1 infection
failed to induce IL-18 secretion are in agreement with this previous
study. HSV-1 has been reported to stimulate multiple inflammasome
adapter proteins in non-macrophage cell types. In HFFs, HSV-1 was shown
to stimulate inflammasome activation through NLRP3 and IFI16 [41] and in keratinocytes it was suggested that HSV-1 activates inflammasomes via NLRP3, IFI16, and AIM2 [40].
However, in our study we found that HSV-1 inflammasome activation in
proinflammatory macrophages is dependent on NLRP3, but not IFI16 or
AIM2. It is possible that different cell types utilize different
inflammasome signaling mechanisms in response to pathogens and that
HSV-1 does activate the inflammasome through IFI16 or AIM2 in
non-macrophage cells. Moreover, the immediate early HSV-1 protein, ICP0,
is known to degrade IFI16, which may explain why IFI16 does not play a
role in inflammasome activation in this model using proinflammatory
macrophages [41,45].
Indeed, we observed decreased IFI16 in THP-1 cells infected with HSV-1
for 24 hours, an effect negated by UV irradiation. Furthermore, the lack
of dependence on IFI16 and AIM2 does not rule out a role for other
dsDNA sensors in HSV-1 inflammasome activation. The NLRP3 inflammasome
can be triggered by a STING mediated mechanism in myeloid cells [49].
Importantly, IFI16, cGAS-STING, and other dsDNA sensors have critical
roles in innate signaling particularly in triggering the type I
interferon response (reviewed in [50]), and sensing by cGAS has also been shown to prime cells for inflammasome activation [51].
Innate sensing of DNA viruses is quite complex, and multiple sensors
can interact, as is the case of IFI16 and cGAS-STING in HFFs [52].
Therefore, it is possible there is redundancy in these dsDNA sensing
molecules and one or more is sensing the viral nucleic acid upstream of
NLRP3. A recent study in which wild-type THP-1 cells were infected with
several strains of HSV-1 showed that more virulent strains of HSV-1
induced more mature IL-18 (measured by western blot) production and that
multiple inflammasome adapter proteins were upregulated after HSV-1
infection, including NLRP3, NLRP6, NLRP12, and IFI16 [18].
However, it is known that HSV-1 infection leads to upregulation of
multiple proinflammatory genes. Therefore, increased expression of these
inflammasome related proteins does not necessarily indicate that
inflammasome activation by HSV-1 is taking place through these adapters [48,50,53]. Although CMV, a closely related herpesvirus, was recently discovered to activate the inflammasome through AIM2 [43], initial studies on HSV-1 inflammasome activation in macrophages did not find a dependence on AIM2 [21].
This finding was explained by the discovery that VP22 specifically
inhibits the interaction between AIM2 and the HSV-1 genome [22].
In agreement with these studies, our current investigation found that
AIM2 was not required for HSV-1 to activate the inflammasome in THP-1
cells. Moreover, UV-irradiated HSV-1 led to more IL-18 production at 24
hours post-infection, suggesting more robust inflammasome signaling in
response to UV-irradiated HSV-1 in both IFNγ stimulated and unstimulated
macrophages. UV-irradiated virus is unable to produce de-novo VP22 and
therefore the virus is able to activate the inflammasome both through
AIM2 and NLRP3. To further support this, the ΔNLRP3 THP-1 cells produced
IL-18 in response to UV-irradiated, but not replication competent
HSV-1. With irradiation, there is insufficient VP22 present to inhibit
AIM2 and thus the macrophages are able to sense the HSV-1 genome via
AIM2. Interestingly, UV-irradiating HSV-1 prior to infection also led to
a robust increase in IL-18 release in the ΔAIM2 THP-1 cell line
compared to WT virus. If the VP22-AIM2 interaction were the only
mechanism by which HSV-1 is capable of inhibiting inflammasome
activation, we would expect no difference in IL-18 production between
ΔAIM2 cells infected with replication competent HSV-1 or UV-irradiated
HSV-1 because AIM2 is not present. However, we found that UV-irradiating
the virus led to an increase in IL-18 in ΔAIM2 THP-1 cells at 24 hours
post infection, suggesting that the virus has evolved other mechanisms
to inhibit inflammasome activation in macrophages that are not AIM2
dependent. This is in agreement with a previous report that HSV-1
interferes with NLRP3-ASC interaction in HFFs [41]. Having multiple mechanisms of evasion highlights the importance of inflammasome activation in macrophages to control HSV-1.
The
primary limitation of our study is that it was restricted to primary
macrophages and macrophage-like cell lines. As discussed, our data
support that HSV-1 is capable of activating more than one inflammasome
signaling adapter and the signaling pathway may differ depending on the
cell type studied. Therefore, we cannot draw conclusions regarding the
interaction between HSV-1 and IFI16 or other inflammasome related
proteins in all cell types the virus is capable of infecting. However,
macrophages are a crucial cell type in inflammasome activation and HSV-1
control in murine models, prompting our focus on this cell type.
Additionally, the present studies were centered on human cells and cell
lines and we did not investigate these inflammasome proteins in other
species or whole animal models. A prior study in mice showed that HSV-1
causes more severe keratitis after corneal infection in NLRP3 KO mice
compared to WT [54].
This suggests that regulation of this pathway is central to the
delicate balance between viral control and excessive tissue damage.
In
summary, we have demonstrated that HSV-1 infection leads to production
of IL-18 through canonical caspase-1 inflammasome activation in
proinflammatory primary human macrophages. This process is dependent on
the inflammasome proteins NLRP3, ASC, and caspase-1. However, IL-1β
release in macrophages infected by HSV-1 occurs through both canonical
and non-canonical inflammasome activation pathways. Furthermore, our
data demonstrate that HSV-1 replication partially inhibits NLRP3
dependent inflammasome activation in human cells.
Materials and methods
Inga kommentarer:
Skicka en kommentar