Herein, we identified that ICH induced a significant increase in ATG transcriptional levels including ATG5, ATG7, and ATG12, which was strongly associated with PTEN mediated FoxO3a nuclear translocation.

PTEN Inhibition Reverses Secondary Hippocampal Injury Post-ICH.

Also, inactivation of the PI3K/AKT/mTOR pathway has been implicated in PTEN induced autophagy initiation [XREF_BIBR, XREF_BIBR].

However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

The S100A8 knockdown using shRNA revealed that COX-2 and PGE 2 expression was regulated by S100A8, which suggested that the intracellular increase of microglial S100A8 levels upregulated COX-2 expression and PGE2 secretion, contributing to neuronal death under hypoxic conditions.

Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

These results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, combined with TLR4 of microglia cells, activated the NLRP3 inflammasome priming.

These results strongly suggested that S100A8 induced the NLRP3 inflammasome priming via NF-kappaB activation.

The results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, triggered the priming of NLRP3 in microglial cells, through the TLR4 and NF-kappaB signaling.

In addition, the translocation of NF-kB, which played a pivotal role in regulating the expression and activation of NLRP3, was also increased when cells were treated with S100A8.

In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis, which was confirmed by immunofluorescence.

However, for the first time, we showed that up-regulation of microglial S100A8 levels increased neuronal apoptosis after hypoxia, in primary multicellular cultures consisting of neurons, astrocytes, and microglia.

Therefore, this study determined whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidated its mechanism of action using in vitro systems, including astrocytes and microglial and neuronal cells, under hypoxic conditions.

S100A8 Knockdown on Microglia Attenuated Neuronal Apoptosis by Hypoxia.

To investigate whether S100A8 expression in microglia induced apoptosis of neuronal cells under hypoxic condition, SH-SY5Y cells were co-cultured with BV-2 cells transfected with S100A8 shRNA for 48 h in a 0.4 mum pore transwell system and under hypoxic conditions (XREF_FIG A, B).

These findings indicated that the expression of S100A8, induced in microglia cells under hypoxic conditions, activated COX-2 expression and PGE 2 secretion to induce the apoptosis of neurons.

Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia.

S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

One study showed that Nuclear Receptor Binding SET Domain Protein 2 (NSD2)-mediated dimethylation of PTEN promotes 53BP1 interactions and subsequent recruitment to sites of DNA-damage sites 75.

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

By using specific mutants of PTEN lacking lipid phosphatase function, an early study concluded that PTEN may block cell migration through a protein phosphatase mediated function on focal adhesion kinase (FAK) protein 14.

PTEN and PDHK1 were observed to have a synthetic-lethal relationship, as loss of PTEN and upregulation of PDHK1 in cells induced glycolysis and a dependency on PDHK1 100.

This PTEN/ARID4B/PI3K signalling axis identifies a novel player in the PTEN mediated suppression of the PI3K pathway and provides a new opportunity to design novel therapeutics to target this axis to promote the tumour suppressive functions of PTEN.

In one of these studies, Baker et al. reported that Notch1 can mediate transcriptional suppression of PTEN, resulting in the derepression of PI3K signalling and development of trastuzumab resistance 91.

This study was the first to link the Ras-MAPK and PI3K pathways through Notch1 transcriptional suppression of PTEN 91.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma 99.

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation 99, thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

Newer studies add to this small body of data, including an intriguing study where a novel PTEN/ARID4B/PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised.

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 (PI3K subunits) 79.

Furthermore, nuclear PTEN directly interacted with and inhibited RNA polymerase II (RNAPII)-mediated transcription, where it was involved in direct downregulation of critical transcriptional control genes including AFF4 and POL2RA 80.

Colocalisation of PTEN and PTENalpha promoted the function of PINK1, a mitochondrial-target kinase, and subsequently promoted energy production 105.

It is known that AKT signaling plays a critical role in the regulation of pre-mRNA splicing 77 and PTEN has been shown to modulate G6PD pre-mRNA splicing in an AKT independent manner 78.

Numb inhibits Notch1, leading to the downregulation of RBP-Jkappa 94, which upregulates PTEN and anti-EMT effectors, leading to the downregulation of p-FAK and pro EMT effectors 94.

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Accordingly, IL-15-dependent expression of perforin and granzyme B was augmented by IL-6, but not other cytokine combinations tested (XREF_SUPPLEMENTARY C-S2E).

Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

IL-2 and IL-15 Induce Cytotoxic Effector Protein Expression in Epidermal CD8 + CD103 + CD49a + Trm Cells.

Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.

This functional dichotomy was evident in the comparison of distinct immune mediated skin diseases, with skin biopsies from vitiligo patients showing a predominance of cytotoxic CD8 + CD103 + CD49a + Trm cells while skin biopsies from psoriasis patients featured the accumulation of the IL-17 producing CD8 + CD103 + CD49a - counterparts.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Generally, IFN-gamma contributes to immunity toward intracellular infections while IL-17 provides anti-fungal defense and both of these cytokines initiate inflammatory keratinocyte responses.

In line withincreased CD49a frequencies, IFN-gamma producing Trm cells were enriched in vitiligo lesions (XREF_FIG G).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

TCR engagement using anti-CD3 antibodies also preferentially induced IFN-gamma by epidermal CD8 + CD103 + CD49a + Trm cells (XREF_FIG D).

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

Revealing functional specialization among epidermal Trm cells with respect to CD49a expression, CD8 + CD103 + CD49a - Trm cells preferentially produced IL-17, a cytokine required for control of bacterial and fungal infections.

Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Corroborating transcriptional profiles, CD8 + CD103 + CD49a - Trm cells produced IL-17 while CD8 + CD103 + CD49a + Trm cells excelled in IFN-gamma production upon stimulation with phorbol 12-myristate 13-acetate and ionomycin (XREF_FIG A-6C).

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Here, we identify CD49a expression as a marker delineating a subpopulation ofCD8 + Trm cells in human skin that specifically localize to thebasal layer of epidermis, preferentially produce IFN-gamma, and display high cytotoxic capacity upon stimulation.

Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

The kinase activity of TAK1 leads to phosphorylation events that activate AP-1 and NF-κB. In parallel to cIAP-induced ubiquitination of RIPK2, XIAP’s enzymatic activity results in the formation of polyubiquitin chains on RIPK2, serving as a platform to engage another E3 ligase complex known as the Linear Ubiquitin Assembly Complex (LUBAC) ( xref , xref ).

K63-linked ubiquitination of RIPK2 has been established as a means to construct protein scaffolds that transduce downstream signaling.

In a step-wise fashion, ubiquitination of RIPK2 leads to activation and recruitment of the TAK1 complex, consisting of TAK1 in association with TAK1-binding protein (TAB)2 and 3.

It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

Conversely, others have shown that overexpression of NLRP7 inhibited pro-IL-1beta synthesis and secretion.

Some studies have suggested that NLRP12 may negatively regulate the NF-kappaB pathway.

IFNgamma functions via signal transducer and activator of transcription 1 (STAT1) and can not induce NLRC5 expression in the absence of STAT1.

Despite this focus, much of the nature of the NOD1 and 2 interaction with these structures remains unknown, although recent findings suggest that NOD2 directly binds MDP with high affinity ( xref ), with the N-glycosylated form specific to the mycobacterial cell wall triggering an exceptionally strong immunogenic response compared to N-acetyl MDP ( xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

While this mechanism is still poorly understood, the ability of NLRP10 to interact with NOD1 as well as its signaling targets RIPK2, TAK1, and NEMO, suggests that NLRP10 may be involved in optimizing cytokine release following bacterial infections.

NOD1 and 2 both interact with RIPK2, via a CARD-CARD homotypic interaction.

In Alzheimer 's disease, amyloid-beta aggregates were shown to activate NLRP3 ex vivo in primary macrophages and microglia.

The possibility of a role for NOD2 in non bacterial infections has also been suggested, with NOD2 having been shown to induce an IFNbeta driven antiviral response following recognition of single stranded viral RNA.

IL-1beta produced downstream of the NLRP3 inflammasome, which is also stimulated by islet amyloid polypeptide, promotes beta-cell dysfunction, and cell death, linking NLRP3 activation to insulin resistance.

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome.

NLRX1 has been shown to enhance ROS production when it is overexpressed, following Chlamydia and Shigella infection, as well as in response to TNFalpha and poly (I : C).

A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

Mutations in NLRP3 were reported to induce an overproduction of IL-1beta that triggers the subsequent development of severe inflammation.

Ceballos-Olvera et al. demonstrated that while IL-18 and pyroptosis are both essential for host resistance, the production of IL-1beta by NLRP3 was deleterious, as it triggered excessive neutrophil recruitment and exacerbated the disease.

Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.

A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

Nlrp6 - / - mice had increased numbers of immune cells in their circulation, as well as enhanced activation of MAPK and NF-kappaB signaling, though Toll like receptor (TLR) activation, suggesting that NLRP6 may suppress TLR pathways after the recognition of pathogens to prevent amplified inflammatory pathology.

Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.

Few ligands have been found for NLRP1 to date, and include bacterial products such as lethal toxin (LT) produced by Bacillus anthracis which activates murine NLRP1b ( xref ), muramyl dipeptide (MDP), a component of bacterial peptidoglycan that activates human NLRP1; and reduced levels of cytosolic ATP ( xref – xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.

Ceramide, a specific product from the metabolism of long-chain saturated fatty acids, and the saturated free fatty acid, palmitate, have been shown to induce IL-1beta in an NLRP3 dependent fashion [Ref.

Crystalline cholesterol was proposed to cause atherosclerosis by acting as a danger signal and initiating inflammation through the NLRP3 inflammasome.

A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68 Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177 Lu-PSMA scintigraphy in a patient with mCRPC.

Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177 Lu-PSMA RLT.

Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68 Ga-PSMA after enzalutamide treatment ( p = 0.004).

Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68 Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177 Lu-PSMA scintigraphy in a patient with mCRPC.

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

In cultured rodent DRG neurons, a mixture of inflammatory mediators including NGF, serotonin, interleukin-1, and bradykinin significantly increase ASIC3 currents, and NGF is known to increase ASIC3 expression.

XREF_BIBR, XREF_BIBR NGF signaling increases ASIC3 expression through a p75NTR dependent transcriptional switch in primary cultured rat DRG neurons.

Evidence suggests that IL-1beta contributes to increased NGF levels in cultured sciatic nerve explants, and inhibiting bradykinin-1 receptor activity blocks NGF induced thermal hyperalgesia in rodents.

XREF_BIBR This NGF mutation also inhibits processing of proNGF to mature NGF, which may lower systemic NGF levels, and abolishes NGF binding to p75NTR.

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. XREF_BIBR These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF induced TrkA phosphorylation and downstream signaling cascades.

These include monoclonal antibodies that bind and neutralize TrkA and small molecule NGF and pro-NGF inhibitors that disrupt NGF and proNGF binding to TrkA and p75NTR.

Upon binding of NGF to the extracellular region of TrkA, the receptor dimerizes, autophosphorylates, and initiates signaling events by docking and phosphorylating downstream targets. xref – xref The NGF-TrkA complex is internalized into endosomes where it can be retrogradely transported, recycled, or degraded. xref Immediate pro-nociceptive effects resulting from NGF/TrkA signaling (such as modulation of ion channel activity) occur in the peripheral nociceptor terminal, while longer-term effects (such as modification of gene expression) occur in the soma following retrograde axonal transport of the NGF/TrkA complex to the DRG. xref , xref Three major signaling cascades initiated by TrkA activation include the phospholipase C-γ (PLCγ) pathway, the mitogen-activated protein kinase (MAPK)/Erk pathway, and the phosphoinositide 3-kinase (PI3K) pathway. xref

NGF null mice have a severe loss of sympathetic and sensory neurons, particularly in the population of peptidergic small- and medium-diameter DRG neurons. xref Animals lacking TrkA receptors show a phenotype similar to NGF null mice, underscoring the importance of NGF-TrkA signaling for the development of the nociceptive system. xref , xref

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

In cultured rodent DRG neurons, for example, Nav1.7 activation is increased via Erk1/2 signaling, and activation of p38 MAPK can directly phosphorylate Nav1.8 leading to an increase in Nav1.8 current density in DRG neurons. xref , xref However, whether these changes to sodium channel activation properties occur downstream of NGF-TrkA signaling, or as part of other signaling pathways, was not explored in these studies.

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

XREF_BIBR - XREF_BIBR The NGF and TrkA complex is internalized into endosomes where it can be retrogradely transported, recycled, or degraded.

XREF_BIBR Immediate pro nociceptive effects resulting from NGF and TrkA signaling (such as modulation of ion channel activity) occur in the peripheral nociceptor terminal, while longer-term effects (such as modification of gene expression) occur in the soma following retrograde axonal transport of the NGF and TrkA complex to the DRG.

XREF_BIBR This mutation does not affect NGF binding to TrkA but does reduce PLC signaling downstream of TrkA.

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

XREF_BIBR TrkA is expressed in nociceptive sensory neurons and is thought to mediate most of the important effects of NGF on the nociceptive system.

Cell culture studies have implicated each of the major signaling pathways downstream of TrkA activation in NGF induced sensitization of TRPV1, though data particularly support a role for PI3K as a mediator of TRPV1 sensitization.

For example, NGF can potentiate the sensitivity of rat DRG neurons to bradykinin.

XREF_BIBR In freshly isolated mouse DRG, NGF exposure increases bradykinin B2 receptor mRNA and membrane expression.

Repeated subcutaneous administration of NGF increases CGRP and substance P release at central afferent terminals of sensory neurons in rodents.

XREF_BIBR NGF contributes to neuronal phenotype by modulating axonal guidance, gene transcription, neurotransmitter release, and synaptic plasticity.

XREF_BIBR, XREF_BIBR NGF can trigger the release of histamine and leukotriene from human basophils, serotonin and histamine from rodent mast cells, and histamine and tryptase from a human mast cell line.

XREF_BIBR A single injection of NGF into the facia of the musculus erector spinae muscle produces both mechanical and chemical (proton) hyperalgesia.

XREF_BIBR Proton gated acid sensing ion channels (ASIC) levels may also be modulated by NGF.

XREF_BIBR In adult rats, BDNF mRNA levels are selectively increased in TrkA expressing DRG cells in response to intrathecal administration of NGF.

Increased mitochondrial Ca2 + concentration ( [ Ca2 + ] ) , in addition to augmented ROS production , induces a reduction of the mitochondrial membrane potential ( DeltaPsim ) in melanocytes and the circulating mononuclear cells of vitiligo patients ( 44 , 72 ) .

Moreover, TNF-alpha inhibits tyrosinase and Trp1 activity, both essential for melanin synthesis.

While its role as an apoptotic mediator has been shown in multiple cell types, in vitiligo, TNF-alpha inhibits melanogenesis by activating the transcription factor NF-kappaB.

These events can thus result in the alteration of the Treg / cytotoxic T cell ratio , impaired Treg differentiation , and increased inflammation in vitiligo .

Increased mitochondrial Ca2 + concentration ( [ Ca2 + ] ) , in addition to augmented ROS production , induces a reduction of the mitochondrial membrane potential ( DeltaPsim ) in melanocytes and the circulating mononuclear cells of vitiligo patients ( 44 , 72 ) .

Increased mitochondrial Ca 2+ concentration ([Ca 2+]), in addition to augmented ROS production, induces a reduction of the mitochondrial membrane potential (DeltaPsim) in melanocytes and the circulating mononuclear cells of vitiligo patients.

High concentrations of H2O2 disrupt melanin synthesis by inhibiting tyrosinase and dihydropteridine reductase ( 71 ) .

Calreticulin, an endoplasmic reticulum (ER) protein that regulates Ca 2+ homeostasis and signaling, is also modulated by H 2 O 2, which increases calreticulin expression and translocation to the cell surface of melanocytes.

Calreticulin, an endoplasmic reticulum (ER) protein that regulates Ca 2+ homeostasis and signaling, is also modulated by H 2 O 2, which increases calreticulin expression and translocation to the cell surface of melanocytes.

This is associated with higher melanocyte apoptosis and production of pro-inflammatory cytokines IL-6 and TNF-α in vitiligo ( xref ).