In a follow-up paper, these researchers found that the NLRP3 inflammasome complex negatively regulated TLR4-TRIF-mediated autophagy by activating caspase-1-induced TRIF cleavage in response to PrP106-126 stimulation.

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

It consists of three main components : an apoptosis associated speck like protein containing a CARD (caspase activation and recruitment domain) (ASC), which functions as a central adaptor protein; an inflammatory caspase, caspase-1, and a pattern recognition receptor (PRR) protein, NLRP3 (nucleotide binding domain (NOD)-like receptor protein 3).

It consists of three main components : an apoptosis associated speck like protein containing a CARD (caspase activation and recruitment domain) (ASC), which functions as a central adaptor protein; an inflammatory caspase, caspase-1, and a pattern recognition receptor (PRR) protein, NLRP3 (nucleotide binding domain (NOD)-like receptor protein 3).

It is worth noting that dopamine has been reported to inhibit NLRP3 inflammasome activation via the dopamine D1 receptor (DRD1), as DRD1 signaling induces the binding of ubiquitin to NLRP3, promoting its degradation ( xref ).

Tau monomers and oligomers could therefore activate the NLRP3 inflammasome, and subsequent injection with fibrillar Abeta containing brain homogenates could induce tau seeding and pathology.

Furthermore, NLRP3 inflammasome-active microglia lead to neuronal cell death in a murine MPTP induced PD model, with KO of NLRP3 being found to protect against dopaminergic neuronal loss in a similar toxin based model, further emphasising the NLRP3 inflammasome 's role in neurodegeneration.

Furthermore, NLRP3 inflammasome-active microglia lead to neuronal cell death in a murine MPTP induced PD model, with KO of NLRP3 being found to protect against dopaminergic neuronal loss in a similar toxin based model, further emphasising the NLRP3 inflammasome 's role in neurodegeneration.

Indirect inhibition of NLRP3 inflammasome activation in 3 x TgAD mice using the fenamate non steroidal anti-inflammatory drug, mefanamic acid, completely abrogated the AD related neuroinflammation, with levels of IL-1beta expression and microglial activation reduced to wild-type levels.

Direct inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, also known as CRID3, improved cognitive function and reduced Abeta accumulation, as well as promoting Abeta clearance in APP and PS1 mice (XREF_FIG).

Direct inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, also known as CRID3, improved cognitive function and reduced Abeta accumulation, as well as promoting Abeta clearance in APP and PS1 mice (XREF_FIG).

Direct inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, also known as CRID3, improved cognitive function and reduced Abeta accumulation, as well as promoting Abeta clearance in APP and PS1 mice (XREF_FIG).

It would be interesting to explore whether NLRP3 inhibition, or the use of other immunosuppressants, could reduce the pathophysiology of HD.

Fyn kinase, in conjunction with CD36, regulates microglial uptake of aggregated alpha-synuclein thereby linking Fyn kinase and CD36 activity to NLRP3 driven inflammation.

This SOD1 (G93A)-mediated inflammation also involved ROS, ATP mediated P2X7 receptor activation, with attenuation by the NLRP3 specific inhibitor MCC950, strongly suggesting that the NLRP3 inflammasome plays an essential role in the process.

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

The ROS inhibitor, N-acetyl-l-cysteine (NAC), significantly reduced IL-1beta production, and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia.

The NLRP3 inflammasome assembles in response to two signals ; toll-like receptor 4 ( TLR4 ) stimulation by LPS induces the NF-kappabeta-mediated transcription of pro-IL-1beta and pro-IL-18 , and stimuli such as P2X7 receptor-facilitated potassium ( K + ) efflux trigger NLRP3 inflammasome activation .

Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET.

Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET.

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era, it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions.

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Mutant p53 and p63 complex can increase RAB coupling protein (RCP)-mediated recycling of cell surface growth promoting receptors.

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog (XREF_FIG).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Further, the human p53 isoform Delta133p53beta lacking the transactivation domain was observed to promote CSC features in breast cancer cell lines by expression of Sox2, Oct3/4, and Nanog in a Delta133p53beta dependent manner.

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Mutant p53 can also promote proliferation by inducing the REG-gamma proteosome pathway in association with p300 (XREF_FIG).

GOF mutant p53 can modify the tumor microenvironment and has been found to support chronic inflammation.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

This underscores the significance of PARP1 inhibitors (PARPi) to augment synthetic lethality in the context of mutant p53 mediated incapacitation of DNA repair (XREF_FIG).

In absence of AMPK, mitochondrial stress augments aerobic glycolysis, also called " Warburg effect " in tumor cells, which is promoted by mutant p53.

Several evidence demonstrate that mutant p53 promotes glycolysis and reprograms the cellular metabolism of cancer cells.

However, whether mutant p53 induced EMT trigger stemness properties in cancer cells, is still quite unexplored.

Gain-of function mutant p53 further promotes EMT and stemness phenotypes by activating genes regulating them.

Although these studies highlight that mutant p53 mediated EMT phenotype confer stemness in cancer cells, however, there is still a lot to explore in context of molecular mechanisms of mutant p53 driven stemness through activation of EMT genes.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

The sustained activation of NF-kB signaling by mutant p53 not only elevate inflammatory response but also protects the cancer cells from cytotoxic effects of tumor microenvironment by activating pro survival pathways.

Interaction of mutant p53 to SREBPs activates mevalonate pathway that promotes invasion in breast cancer cells (XREF_FIG).

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Similarly, p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs.

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Additionally, TLR4 signaling can be limited by the tyrosine phosphatases SHP1 and SHP2.

A number of preclinical studies have demonstrated that TLR4 gene deficiency or inhibition ameliorated renal function, decreased histological damage and reduced inflammation, oxidative stress and cell death in different types of AKI.

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10 .

Specifically , TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation , thus decreasing downstream signaling [ 106,107 ] .

Besides its effects targeting Nrf2, sulforaphane specifically suppresses oligomerization of TLR4 and decrease inflammatory response [XREF_BIBR].

Glucose induces TLR4 expression in podocytes and tubular cells and increases inflammation, renal injury and fibrosis in diabetes nephropathy, effects that were not observed in TLR4 deficient mice [XREF_BIBR].

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10.

On the other hand, IL-10, throughout miR-146b, reduces the expression of TLR4, MyD88, IRAK1 and TRAF6 [XREF_BIBR].

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10.

Specifically, TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation, thus decreasing downstream signaling [XREF_BIBR, XREF_BIBR].

Resveratrol, a natural phytoalexin, also reduced TLR4 expression and NFkappaB activation in macrophages and mice with LPS induced AKI [XREF_BIBR].

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The assembly with sTLR4 prevented the interaction of ligands and coreceptors with transmembrane TLR4, therefore efficiently attenuating TLR4 activation.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The interaction between LPS and both systemic and renal TLR4 has been reported in SI-AKI [XREF_BIBR].

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms .

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms.

CD14 transfers LPS to MD-2, a beta-cup folded protein necessary for LPS mediated TLR4 dimerization.

Specifically, TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation, thus decreasing downstream signaling [XREF_BIBR, XREF_BIBR].

TLR4 mediated MyD88 dependent signaling pathway requires the initial interaction with the sorting adaptor TIRAP (TIR domain containing adapter protein), present in regions enriched with phosphatidylinositol 4,5-bisphosphate, such as lipid rafts [XREF_BIBR, XREF_BIBR].

Upon ligand binding, TLR4 homodimerizes and initiates intracellular signaling through two major downstream pathways : (1) from the plasma membrane, the MyD88 dependent pathway, which activates early NFkappaB activation and cytokines production, and (2) from the endosome, the MyD88 independent TRIF dependent pathway, which upregulates type I IFNs and a late phase NFkappaB activation [XREF_BIBR, XREF_BIBR] (XREF_FIG).

TLR4 Mediated Effects TLR4 is a key molecule involved in the pathogenesis of inflammatory diseases [ 63,64 ] .

Moreover, TLR4 mediated expression of cell adhesion molecules (ICAM-1 and E-selectin) may contribute to renal leucocyte infiltration and renal injury in SI-AKI [XREF_BIBR, XREF_BIBR].

Additionally, TLR4 recognition of DAMPs in damaged tissues further contributes to local inflammation and fibrosis [XREF_BIBR].

Glucose induces TLR4 expression in podocytes and tubular cells and increases inflammation, renal injury and fibrosis in diabetes nephropathy, effects that were not observed in TLR4 deficient mice [XREF_BIBR].

In addition to these data, NOX4 collaborated with TLR4 mediated apoptosis in renal I/R [XREF_BIBR].

CD14 transfers LPS to MD-2, a beta-cup folded protein necessary for LPS mediated TLR4 dimerization.

CD14 plays a key role in LPS mediated TLR4 endocytosis [XREF_BIBR].

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Additionally, TLR4 signaling can be limited by the tyrosine phosphatases SHP1 and SHP2.

A number of preclinical studies have demonstrated that TLR4 gene deficiency or inhibition ameliorated renal function, decreased histological damage and reduced inflammation, oxidative stress and cell death in different types of AKI.

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10 .

Specifically , TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation , thus decreasing downstream signaling [ 106,107 ] .

Besides its effects targeting Nrf2, sulforaphane specifically suppresses oligomerization of TLR4 and decrease inflammatory response [XREF_BIBR].

Glucose induces TLR4 expression in podocytes and tubular cells and increases inflammation, renal injury and fibrosis in diabetes nephropathy, effects that were not observed in TLR4 deficient mice [XREF_BIBR].

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10.

On the other hand, IL-10, throughout miR-146b, reduces the expression of TLR4, MyD88, IRAK1 and TRAF6 [XREF_BIBR].

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10.

Specifically, TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation, thus decreasing downstream signaling [XREF_BIBR, XREF_BIBR].

Resveratrol, a natural phytoalexin, also reduced TLR4 expression and NFkappaB activation in macrophages and mice with LPS induced AKI [XREF_BIBR].

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The assembly with sTLR4 prevented the interaction of ligands and coreceptors with transmembrane TLR4, therefore efficiently attenuating TLR4 activation.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The interaction between LPS and both systemic and renal TLR4 has been reported in SI-AKI [XREF_BIBR].

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms .

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms.

CD14 transfers LPS to MD-2, a beta-cup folded protein necessary for LPS mediated TLR4 dimerization.

Specifically, TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation, thus decreasing downstream signaling [XREF_BIBR, XREF_BIBR].

Upon ligand binding, TLR4 homodimerizes and initiates intracellular signaling through two major downstream pathways : (1) from the plasma membrane, the MyD88 dependent pathway, which activates early NFkappaB activation and cytokines production, and (2) from the endosome, the MyD88 independent TRIF dependent pathway, which upregulates type I IFNs and a late phase NFkappaB activation [XREF_BIBR, XREF_BIBR] (XREF_FIG).

TLR4 mediated MyD88 dependent signaling pathway requires the initial interaction with the sorting adaptor TIRAP (TIR domain containing adapter protein), present in regions enriched with phosphatidylinositol 4,5-bisphosphate, such as lipid rafts [XREF_BIBR, XREF_BIBR].

TLR4 Mediated Effects TLR4 is a key molecule involved in the pathogenesis of inflammatory diseases [ 63,64 ] .

Moreover, TLR4 mediated expression of cell adhesion molecules (ICAM-1 and E-selectin) may contribute to renal leucocyte infiltration and renal injury in SI-AKI [XREF_BIBR, XREF_BIBR].

Additionally, TLR4 recognition of DAMPs in damaged tissues further contributes to local inflammation and fibrosis [XREF_BIBR].

Glucose induces TLR4 expression in podocytes and tubular cells and increases inflammation, renal injury and fibrosis in diabetes nephropathy, effects that were not observed in TLR4 deficient mice [XREF_BIBR].

In addition to these data, NOX4 collaborated with TLR4 mediated apoptosis in renal I/R [XREF_BIBR].

Some of these TLR4 inhibitors have strong anti-inflammatory effects and prevent cytokine production in these diseases , such as Eritoran , NI-0101 , CX-01 and JKB-121 [ 242 ] .

CD14 transfers LPS to MD-2, a beta-cup folded protein necessary for LPS mediated TLR4 dimerization.

CD14 plays a key role in LPS mediated TLR4 endocytosis [XREF_BIBR].

The activation of the A 1 AR promotes osteoclast differentiation reducing the MSC-osteoblast differentiation.

Herein, we report an OFMT with unusual morphology and non-specific immunoprofile harboring a novel MEAF6-SUZ12 fusion.

Novel MEAF6-SUZ12 fusion in ossifying fibromyxoid tumor with unusual features.

Interestingly, we found that knockdown of either MICAL2 or MRTF-A suppressed the activity of CDC42, whereas this effect was reversed by overexpression of either MICAL2 or MRTF-A.

Interestingly, we found that knockdown of either MICAL2 or MRTF-A suppressed the activity of CDC42, whereas overexpression of both induced the opposite effect (XREF_FIG).

The precise mechanism underlying the MICAL2 and MRTF-A-induced activation of CDC42 in gastric cancer cells requires further investigation.

Silencing of CDC42 markedly inhibits the migration and invasion of gastric cancer cells.

Interestingly, we found that knockdown of either MICAL2 or MRTF-A suppressed the activity of CDC42, whereas this effect was reversed by overexpression of either MICAL2 or MRTF-A.

Interestingly, we found that knockdown of either MICAL2 or MRTF-A suppressed the activity of CDC42, whereas overexpression of both induced the opposite effect (XREF_FIG).

These results indicated that MICAL2 may promote gastric cancer cell migration through MRTF-A-dependent CDC42 activation and MMP9 expression.

MICAL2 Induces MRTF-A-Dependent CDC42 Activation and MMP9 Expression.

Furthermore, MICAL2 facilitates gastric cancer cell migration by promoting MRTF-A-dependent activation of cell division control protein 42 homolog (CDC42) and expression of MMP9.

Moreover, silencing of MRTF-A inhibited the CDC42 activation induced by overexpression of MICAL2.

In this study, we found that knockdown of MRTF-A prevented the upregulation of CDC42 activation in the MICAL2 overexpressing cells.

Neonatal mice deficient in TLR4 have decreased LGR5+ stem cell proliferation and crypt fission compared to wild type mice.

Neonatal mice deficient in TLR4 have markedly diminished LGR5+ stem cell proliferation and diminished crypt fission.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE₂ production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

In contrast, TLR4 activation by LMW-HA requires a TLR4-MD2 complex but is independent of CD14 and LPS binding protein.

TLR4 activation by LPS requires a TLR4-MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4-MD2 complex ( xref , xref ).

In contrast, TLR4 activation by LMW-HA requires a TLR4 and MD2 complex but is independent of CD14 and LPS binding protein.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

There is evidence that LMW-HA binds both CD44 and TLR4.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44-TLR4 complex ( xref , xref ).

This suggests that endogenous HA binding to both CD44 and TLR4 promotes intestinal growth.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44 and TLR4 complex.

Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE 2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation.

Although most studies suggest that HMW-HA binds CD44 and LMW-HA binds TLR2 and TLR4.

TLR2 and TLR4 binding to LMW-HA promotes the production of proinflammatory cytokines including TNFα, MIP, IL-1β, IL-6, and IL-12 ( xref , xref – xref ).

TLR2 and TLR4 preferentially bind to LMW-HA.

This review addresses two novel related intercellular pathways in which a host molecule, HA, binding to TLR2 and TLR4 drives physiologic processes in the intestine and colon.

This suggests that endogenous HA binding to TLR2 and TLR4 blocks bleomycin-induced apoptosis.

Among the PAMPs are lipoteichoic acid (LTA), a component of gram positive bacteria that binds TLR2, and LPS, a component of gram negative bacteria that binds TLR4.

PGE₂ binding to EP2 blocks radiation-induced apoptosis by an AKT-EGFR mechanism ( xref ).

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

HA binds to CD44, TLR2, TLR4, the receptor for HA mediated motility (RHAMM), layilin, lymphatic vessel endothelial HA receptor- 1 (LYVE-1), and HA receptor for endocytosis.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

EGFR can activate beta-catenin via the receptor tyrosine kinase-PI3K-Akt pathway.

EGFR can activate β-catenin via the receptor tyrosine kinase-PI3K-Akt pathway ( xref ).

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

In contrast to wound repair, where inflammation accompanies enhanced epithelial proliferation driven by TLR2 and TLR4 activation, in intestinal growth TLR4 activation promotes epithelial proliferation in the absence of inflammation.

This suggests that TLR2 and TLR4 signaling driven by PAMPs from commensal bacteria promotes epithelial proliferation during wound repair in the colon.

In contrast , in adult mice TLR2 / TLR4 activation on pericryptal macrophages by exogenous HA or other TLR2 / TLR4 agonists results in CXCL12 production resulting in the migration of COX-2 expressing MSCs .

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

TLR4 activation by LPS and LMW-HA require different accessory molecules.

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

In human biliary carcinoma cells in vitro, addition of LPS initiates a positive feedback loop of TLR4 activation, PGE2 production through COX-2 and EGFR activation.

Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW - HA , TLR4 activation by either one promotes wound healing ( 12 , 27 , 28 , 33 ) .

TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .

TLR4 activation by LPS and LMW-HA require different accessory molecules .

Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .

Activation of TLR2 by LTA or activation of TLR4 by LPS or HA results in the release of the chemokine CXCL12 , which binds to CXCR4 on COX-2 expressing MSCs .