Toll-like receptor 4: A promising crossroads in the diagnosis and treatment of several pathologies

García, Miguel Martínez; Goicoechea, C.; Molina-Álvarez, Miguel; Pascual, David W.

doi:10.1016/j.ejphar.2020.172975

Cited by 40 publications

(32 citation statements)

References 160 publications

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“…32 Among the members of the TLR family, TLR4 in particular is abundantly expressed in various organs and plays an important role in innate immunity by binding many exogenous and endogenous ligands, leading to acute inflammatory reactions. 33 Consistent with previous reports that TLR4 plays a role in the IR injury in multiple organs, our current results showed that TLR4 levels were significantly upregulated in response to IR insult in a time-dependent manner, with peak expression at 2-4 hours. 34 After confirming that TLR4 downregulation was involved in melatonin-induced autophagy, we next utilized TAK-242 and CRX-527 to further validate the role of TLR4 signaling.…”

Section: Discussionsupporting

confidence: 93%

“…Toll‐like receptors were first found to recognize pathogen‐associated molecular patterns (PAMPs) in mammals; furthermore, PAMPs have been characterized as sentinels of tissue damage and triggers of the inflammatory cascade 32 . Among the members of the TLR family, TLR4 in particular is abundantly expressed in various organs and plays an important role in innate immunity by binding many exogenous and endogenous ligands, leading to acute inflammatory reactions 33 . Consistent with previous reports that TLR4 plays a role in the IR injury in multiple organs, our current results showed that TLR4 levels were significantly upregulated in response to IR insult in a time‐dependent manner, with peak expression at 2‐4 hours 34 .…”

Section: Discussionmentioning

confidence: 99%

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Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

et al. 2020

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Autophagy is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia‐reperfusion (IR) injury. In this study, renal IR was induced in female C57BL/6 mice after melatonin administration. Renal function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity, autophagy changing, apoptosis levels, and autophagy‐associated intracellular signaling pathway were assessed to evaluate the impact of antecedent melatonin treatment on IR‐induced renal injury. The administration of melatonin resulted in significantly preserved renal function, and the protective effect was associated with ameliorated oxidative stress, limited pro‐inflammatory cytokine production, and neutrophil and macrophage infiltration. Moreover, autophagic flux was increased after melatonin administration while the apoptosis levels were decreased in the melatonin‐pretreated mice. Using TAK‐242 and CRX‐527, we confirmed that MyD88‐dependent TLR4 and MEK/ERK/mTORC1 signaling participated in melatonin‐induced autophagy in IR mice. Collectively, our results provide novel evidence that antecedent melatonin treatment provides protection for the kidney against IR injury by enhancing autophagy, as regulated by the TLR4/MyD88/MEK/ERK/mTORC1 signaling pathway. Therefore, melatonin preconditioning offers a potential therapeutic approach to prevent renal IR injury related to various clinical conditions.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

et al. 2020

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“…TLR4 activates overlapping signaling pathways, yet has distinct sets of target genes from other membrane receptors 28 . Exploration of the structural details of TLR4 revealed the existence of an extracellular leucine‐rich repeat (LRR) domain, a transmembrane domain, and an intracellular Toll‐interleukin (IL)‐1 receptor (TIR) domain 29 .…”

Section: Discussionmentioning

confidence: 99%

“…TLR4 activates overlapping signaling pathways, yet has distinct sets of target genes from other membrane receptors. 28 TLR4 was pivotal promoter of inflammation which related NF-kB and C3 signaling, and then released TNF-α and ILs, which can induce apoptosis of osteosarcoma cells. 10,11,31,32 However, whether the role of COLEC12 for inflammation in osteosarcoma is regulated by TLR4…”

Section: F I G U R Ementioning

confidence: 99%

COLEC12 regulates apoptosis of osteosarcoma through Toll‐like receptor 4–activated inflammation

Deng

et al. 2020

Clinical Laboratory Analysis

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“…8,11 In the context of MOC31PE being administered intraperitoneally after surgery, tumor-related ICD could be reinforced by endogenous factors upon release of damage-associated molecular patterns (DAMPs) from cells in the peritoneal cavity. 12 DAMPs, e.g., calreticulin and high-mobility group protein B1 (HMGB1), 13,14 are released after comprehensive surgery with subsequent activation of the inflammatory cascade through Toll-like receptor 4 and its coreceptor CD14, 15,16 subsequently inducing production and release of a range of cytokines, such as TNF, IL-1b, IL-6, IL-8, and IL-10. 17,18 Potentiation of MOC31PE's effect by endogenous DAMPs could therefore contribute to the magnitude of inflammation and potential antitumor effects.…”

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confidence: 99%

Increased Local Inflammatory Response to MOC31PE Immunotoxin After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

et al. 2021

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Background Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial cell adhesion molecule, and kills cancer cells by distinct mechanisms, simultaneously causing immune activation by induction of immunogenic cell death (ICD). Methods Systemic and local cytokine responses were analyzed in serum and intraperitoneal fluid samples collected the first three postoperative days from clinically comparable patients undergoing CRS-HIPEC with (n = 12) or without (n = 26) intraperitoneal instillation of MOC31PE. A broad panel of 27 pro- and antiinflammatory interleukins, chemokines, interferons, and growth factors was analyzed using multiplex technology. Results The time course and magnitude of the systemic and local postoperative cytokine response after CRS-HIPEC were highly compartmentalized, with modest systemic responses contrasting substantial intraperitoneal responses. Administration of MOC31PE resulted in changes that were broader and of higher magnitude compared with CRS-HIPEC alone. Significantly increased levels of innate proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF) as well as an interesting time response curve for the strong T-cell stimulator interferon (IFN)-γ and its associated chemokine interferon gamma-induced protein/chemokine (C-X-C motif) ligand 10 (IP-10) were detected, all associated with ICD. Conclusions Our study revealed a predominately local rather than systemic inflammatory response to CRS-HIPEC, which was strongly enhanced by MOC31PE treatment. The MOC31PE-induced intraperitoneal inflammatory reaction could contribute to improve remnant cancer cell killing, but the mechanisms remain to be elucidated in future studies.

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Toll-like receptor 4: A promising crossroads in the diagnosis and treatment of several pathologies

Cited by 40 publications

References 160 publications

Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

COLEC12 regulates apoptosis of osteosarcoma through Toll‐like receptor 4–activated inflammation

Increased Local Inflammatory Response to MOC31PE Immunotoxin After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

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