TLR4 and TNFR1 blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype

Sawoo, Ritasha; Dey, Rajen; Ghosh, Rituparna; Bishayi, Biswadev

doi:10.1007/s12026-021-09209-0

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…During the later stages, activated macrophages are responsible for the resolution of inflammation, fibroproliferative response regulation, wound healing, and tissue repair (11)(12)(13)(14). Based on the interaction with specific stimuli and the following gene expression, transcriptional and post-transcriptional regulation, and mediator secretion, two main activated profiles of macrophages have been recognized: classically activated proinflammatory M1 macrophages (15-19) and alternatively activated anti-inflammatory M2 macrophages (11,(17)(18)(19)(20)(21)(22), as shown in Figure 1.…”

Section: Activation Of Macrophagesmentioning

confidence: 99%

“…The effect of LPS on macrophages promotes the activation of transcription factors, such as nuclear factor kappa-light-chain enhancer of B-cell (NF-kB) (22)(23)(24)(25)(26), signal transducer and activator of transcription molecules (STAT1/3) (23)(24)(25), hypoxia-induced factor (HIF)-1a (27)(28)(29)(30), and activator protein (AP)-1 (25). This transcriptional activation leads to the secretion of high levels of pro-inflammatory cytokines, such as TNF-a, interleukin (IL)-1b, IL-6, IL-12, and IL-23, as well as reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) (31,32), which are characteristic of the M1 polarization and are necessary to sustain the inflammatory reaction and recruit other immune cells to initiate the adaptive immune response.…”

Section: Activation Of Macrophagesmentioning

confidence: 99%

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Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages

Marrocco

Ortiz

2022

Front. Immunol.

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In the lungs, macrophages constitute the first line of defense against pathogens and foreign bodies and play a fundamental role in maintaining tissue homeostasis. Activated macrophages show altered immunometabolism and metabolic changes governing immune effector mechanisms, such as cytokine secretion characterizing their classic (M1) or alternative (M2) activation. Lipopolysaccharide (LPS)-stimulated macrophages demonstrate enhanced glycolysis, blocked succinate dehydrogenase (SDH), and increased secretion of interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Glycolysis suppression using 2 deoxyglucose in LPS-stimulated macrophages inhibits IL-1β secretion, but not TNF-α, indicating metabolic pathway specificity that determines cytokine production. In contrast to LPS, the nature of the immunometabolic responses induced by non-organic particles, such as silica, in macrophages, its contribution to cytokine specification, and disease pathogenesis are not well understood. Silica-stimulated macrophages activate pattern recognition receptors (PRRs) and NLRP3 inflammasome and release IL-1β, TNF-α, and interferons, which are the key mediators of silicosis pathogenesis. In contrast to bacteria, silica particles cannot be degraded, and the persistent macrophage activation results in an increased NADPH oxidase (Phox) activation and mitochondrial reactive oxygen species (ROS) production, ultimately leading to macrophage death and release of silica particles that perpetuate inflammation. In this manuscript, we reviewed the effects of silica on macrophage mitochondrial respiration and central carbon metabolism determining cytokine specification responsible for the sustained inflammatory responses in the lungs.

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Section: Activation Of Macrophagesmentioning

confidence: 99%

Section: Activation Of Macrophagesmentioning

confidence: 99%

Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages

Marrocco

Ortiz

2022

Front. Immunol.

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“…Considering the superoxide and nitric oxide production levels measured from the peritoneal fluid, it was found that the high levels of NO and superoxide recorded on LPS stimulation were downregulated because of the administration of DEX indicating antiinflammatory effects. Blocking of the receptors too lowered the NO and superoxide production, which might be an indicator of reduced inflammation as supported by another recent study (Sawoo, Dey, Ghosh, & Bishayi, 2021). Inducible nitric oxide synthase (iNOS) and arginase 1 (ARG1) are regarded as marker enzymes and crucial determining factors for M1 and M2 switching respectively during LPSinduced sepsis (Viola, Munari, Sánchez-Rodríguez, Scolaro, & Castegna, 2019).…”

Section: Discussionmentioning

confidence: 76%

Exogenous IL‐10 posttreatment along with TLR4 and TNFR1 blockade improves tissue antioxidant status by modulating sepsis‐induced macrophage polarization

Sawoo

Dey

Ghosh

et al. 2023

J of Applied Toxicology

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Multi‐organ dysfunction is one of the major reasons behind the high mortality of sepsis throughout the world. With the pathophysiology of sepsis remaining largely unknown, the uncontrolled reactive oxygen species (ROS) production along with the decreased antioxidants contributes to the progression toward septic shock. Being the effector cells of the innate immunity system, macrophages secrete both pro‐inflammatory and anti‐inflammatory mediators during inflammation. Lipopolysaccharide (LPS) binding to toll‐like receptor 4 (TLR4) releases TNF‐α, which initiates pro‐inflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling. However, it is counteracted by the anti‐inflammatory interleukin 10 (IL‐10) causing decreased oxidative stress. Our study thus aimed to assess the effects of exogenous IL‐10 treatment post‐neutralization of TLR4 and TNFR1 (by anti‐TLR4 antibody and anti‐TNFR1 antibody, respectively) in an in vivo murine model of LPS‐sepsis. We have also examined the tissue‐specific antioxidant status in the spleen, liver, and lungs along with the serum cytokine levels in adult male Swiss albino mice to determine the functional association with the disease. The results showed that administration of recombinant IL‐10 post‐neutralization of the receptors was beneficial in shifting the macrophage polarization to the anti‐inflammatory M2 phenotype. IL‐10 treatment significantly downregulated the free radicals production resulting in diminished lipid peroxidase (LPO) levels. The increased antioxidant activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GRX) conferred protection against LPS‐induced sepsis. Western blot data further confirmed diminished expressions of TLR4 and TNFR1 along with suppressed stress‐activated protein kinases/Jun amino‐terminal kinases (SAPK/JNK) and increased SOD and CAT expressions, which altogether indicated that neutralization of TLR4 and TNFR1 along with IL‐10 posttreatment might be a potential therapeutic measure for the treatment of sepsis.

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“…We hypothesized that this might be attributed to toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1) blockade. [48] In addition, we quantified the levels of TNF-𝛼, NO, and VEGF in cell culture supernatants, which are cytokines secreted by M1 and M2 macrophages, respectively. [49] The secretion of the proinflammatory factor TNF-𝛼 by M1 macrophages was significantly attenuated to the level of 19.60 ± 4.02 pg mL −1 following treatment with the HA@Cur@Ag hydrogel (Figure 5E).…”

Section: Anti-inflammatory Capacity Of Hydrogels In Vitromentioning

confidence: 99%

Hyaluronic Acid‐Based Reactive Oxygen Species‐Responsive Multifunctional Injectable Hydrogel Platform Accelerating Diabetic Wound Healing

Shi,

Zhang,

et al. 2023

Adv Healthcare Materials

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Diabetic wounds are more likely to develop into complex and severe chronic wounds. The objective of this study is to develop and assess a reactive oxygen species (ROS)‐responsive multifunctional injectable hydrogel for the purpose of diabetic wound healing. We successfully synthesized a multifunctional hydrogel (HA@Cur@Ag) with dual antioxidant, antibacterial, and anti‐inflammatory properties by crosslinking thiol hyaluronic acid (SH‐HA) and disulfide‐bonded hyperbranched polyethylene glycol (HB‐PBHE) through Michael addition while incorporating curcumin liposomes and silver nanoparticles (AgNPs). The HA@Cur@Ag hydrogel exhibited favourable biocompatibility, degradability and injectivity. The outcomes of in vitro and in vivo experiments demonstrated that the hydrogel could effectively be loaded with and release curcumin liposomes, as well as silver ions, thereby facilitating diabetic wound healing through multiple mechanisms, including ROS scavenging, bactericidal activity, anti‐inflammatory effects, and the promotion of angiogenesis. Transcriptome sequencing revealed that the HA@Cur@Ag hydrogel effectively suppressed the activation of the tumour necrosis factor (TNF)/ nuclear factor κB (NF‐κB) pathway to ameliorate oxidative stress and inflammation in diabetic wounds. These findings suggested that this ROS‐responsive multifunctional injectable hydrogel, which possessed the ability to precisely coordinate and integrate intricate biological and molecular processes involved in wound healing, exhibited notable potential for expediting diabetic wound healing.This article is protected by copyright. All rights reserved

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TLR4 and TNFR1 blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype

Cited by 14 publications

References 62 publications

Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages

Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages

Exogenous IL‐10 posttreatment along with TLR4 and TNFR1 blockade improves tissue antioxidant status by modulating sepsis‐induced macrophage polarization

Hyaluronic Acid‐Based Reactive Oxygen Species‐Responsive Multifunctional Injectable Hydrogel Platform Accelerating Diabetic Wound Healing

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