TIR-domain-containing Adapter-inducing Interferon-β Research Articles

Paediatric obstructive sleep apnoea syndrome (OSAS) is associated with tonsil colonisation by Streptococcus pyogenes

The involvement of pathogenic bacteria in obstructive sleep apnoea syndrome (OSAS) has yet to be elucidated. We investigated the possible role of group A streptococcus (GAS) in OSAS pathogenesis. In 40 tonsillectomized patients affected by OSAS and 80 healthy controls, significant (p < 0.0001) association of GAS with paediatric OSAS was found. Supernatant from streptolysin O (SLO)-producing GAS induced production of cysteinyl leukotrienes (CysLTs) in tonsil mononuclear cells (TMCs). CysLTs-treated TMCs showed significant (p < 0.05) proliferation of CD4+ T, CD19+ and CD19+CD27+CD38+ B lymphocytes. We discovered a SLO-dependent activation of CysLTs production through a pathway involving TOLL-like receptor 4 (TLR4), TIR-domain-containing adapter-inducing interferon-β (TRIF), Myeloid differentiation primary response gene 88 (MyD88), and p38 MAP Kinase. In conclusion, we hypothesise that GAS may contribute to paediatric tonsillar hyperplasia through CysLTs production induced by SLO, and this might explain its association with OSAS.

WISP1 mediates hepatic warm ischemia reperfusion injury via TLR4 signaling in mice

Wnt-induced secreted protein-1 (WISP1) is an extracellular matrix protein that has been reported in cancer researches. Our previous studies on WISP1 implied it could be a harmful mediator in septic mice. However, its role in liver ischemia reperfusion (I/R) injury is unknown. This study investigated the effects of WISP1 on liver I/R damage. Male C57BL/6 wild-type mice were used to undergo 60 min segmental (70%) ischemia. WISP1 expression was measured after indicated time points of reperfusion. Anti-WISP1 antibody was injected intraperitoneally to mice. Toll-like receptor 4 (TLR4) knockout mice and TIR-domain-containing adaptor inducing interferon-β (TRIF) knockout mice were adopted in this study. WISP1 was significantly enhanced after 6 h of reperfusion when compared with sham treated mice and significantly decreased either by TLR4 knockout mice or TRIF knockout mice. Anti-WISP1 antibody significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), pathological changes and pro-inflammatory cytokine levels in the mice following I/R. Furthermore, significantly increased serum transaminase levels were found in C57 wild-type mice treated with recombinant WISP1 protein, but not found in TLR4 knockout or TRIF knockout mice subjected to liver I/R. Taken together, WISP1 might contribute to hepatic ischemia reperfusion injury in mice and possibly depends on TLR4/TRIF signaling.

1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine Suppresses Toll-Like Receptor 4 Dimerization Induced by Lipopolysaccharide

Toll-like receptor 4 (TLR4) recognizes LPS and triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter, inducing interferon-β (TRIF)-dependent major downstream signaling pathways. Previously, we presented biochemical evidence that 1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), which was synthesized in our laboratory, inhibits NF-κB activation induced by LPS. Here, we investigated whether FPP modulates the TLR4 downstream signaling pathways and what anti-inflammatory target in TLR4 signaling is regulated by FPP. FPP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization. These results suggest that FPP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression.

Royal Sun Medicinal Mushroom, Agaricus brasiliensis (Agaricomycetidae), Derived Polysaccharides Exert Immunomodulatory Activities In Vitro and In Vivo.

The royal sun mushroom, Agaricus brasiliensis is a widely consumed mushroom around the world. In this study, the immunoregulatory potential of A. brasiliensis polysaccharides was investigated in vitro and in vivo. In vivo, the polysaccharides remarkably increased the spleen and thymus indexes in mice, and this effect was influenced significantly by age (the adult and the juvenile). The spleen index increased by 27.28% in adult mice treated with the polysaccharides, whereas the increase in juvenile mice was just 12.59% at the dose of 150 mg·kg-1·d-1. Moreover, the effect of the polysaccharides on the thymus and spleen indexes in adult mice was obvious both in males and females. The carbon clearance ability (phagocytic index) was improved with increasing doses, (32.81% at 120 mg·kg-1·d-1, and 38.34% at 150 mg·kg-1·d-1) in mice treated with the polysaccharides. In vitro, the polysaccharides increased the RAW264.7 cell proliferation with 34.78% at 25 µg/mL and 26.78% at 50 µg/mL. Furthermore, the polysaccharides also promoted mRNA expressions of interleukin (IL)-6, IL-1β, cyclooxygenase-2, and Toll-like receptor 4 (TLR4), myeloid differentiation 88 (MYD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF) in the cells, indicating that the polysaccharides induce the secretion of inflammatory cytokines by stimulating TLR4/MyD88 and TLR4/TRIF pathways. In conclusion, these results suggest that A. brasiliensis polysaccharides induce a very promising immunostimulation effect in vivo and in vitro. Therefore, it should be explored as a novel natural functional food additive.

Anti-inflammatory effect of streptochlorin via TRIF-dependent signaling pathways in cellular and mouse models

Streptochlorin, a small compound derived from marine actinomycete, has been shown to have anti-angiogenic, anti-tumor, and anti-allergic activities. However, the anti-inflammatory effects and underlying mechanisms have not yet been reported. In the present study, we investigated the effect of streptochlorin on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. As shown in Fig. 1, streptochlorin attenuated the production of proinflammatory mediators such as nitric oxide, cyclooxygenase-2, pro-interleukin (IL)-1β, and IL-6 in LPS-stimulated RAW264.7 cells through inhibition of the Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling pathway. IC50 to inhibit those inflammatory mediators is 25 µM.

Prothymosin‐alpha preconditioning activates TLR4–TRIF signaling to induce protection of ischemic retina

Prothymosin-alpha protects the brain and retina from ischemic damage. Although prothymosin-alpha contributes to toll-like receptor (TLR4)-mediated immnunopotentiation against viral infection, the beneficial effects of prothymosin-alpha-TLR4 signaling in protecting against ischemia remain to be elucidated. In this study, intravitreal administration of prothymosin-alpha 48 h before induction of retinal ischemia prevented retinal cellular damage as evaluated by histology, and retinal functional deficits as evaluated by electroretinography. Prothymosin-alpha preconditioning completely prevented the ischemia-induced loss of ganglion cells with partial survival of bipolar and photoreceptor cells, but not amacrine cells, in immunohistochemistry experiments. Prothymosin-alpha treatment in the absence of ischemia caused mild activation, proliferation, and migration of retinal microglia, whereas the ischemia-induced microglial activation was inhibited by prothymosin-alpha preconditioning. All these preventive effects of prothymosin-alpha preconditioning were abolished in TLR4 knock-out mice and by pre-treatments with anti-TLR4 antibodies or minocycline, a microglial inhibitor. Prothymosin-alpha preconditioning inhibited the retinal ischemia-induced up-regulation of TLR4-related injury genes, and increased expression of TLR4-related protective genes. Furthermore, the prothymosin-alpha preconditioning-induced prevention of retinal ischemic damage was abolished in TIR-domain-containing adapter-inducing interferon-β knock-out mice, but not in myeloid differentiation primary response gene 88 knock-out mice. Taken together, the results of this study suggest that prothymosin-alpha preconditioning selectively drives TLR4-TIR-domain-containing adapter-inducing interferon-β signaling and microglia in the prevention of retinal ischemic damage. We propose the following mechanism for prothymosin-alpha (ProTα) preconditioning-induced retinal prevention against ischemia: ProTα preconditioning-induced prevention of retinal ischemic damage is mediated by selective activation of the TIR-domain-containing adapter-inducing interferon-β (TRIF)- interferon regulatory factor 3 (IRF3) pathway downstream of toll-like receptor 4 (TLR4) in microglia, resulting in up-regulation of TRIF-IRF3-dependent protective genes and down-regulation of myeloid differentiation primary response gene 88 (MyD88)-Nuclear factor (NF)κB-dependent injury genes. Detailed investigations would be helpful to test the efficacy of ProTα as a therapeutic agent for the prevention of ischemic disorders.

Role of the Toll‑like receptor3 signaling pathway in the neuroprotective effect of sevoflurane pre‑conditioning during cardiopulmonary bypass in rats.

The aim of the present study was to explore the roles and possible molecular mechanism of the alleviating effect of sevoflurane pre-treatment on the extracorporeal circulation and to investigate the possible involvement of the Toll-like receptor (TLR3) signaling pathway. A total of 64 male Sprague Dawley rats were randomly divided into three groups: The sham operation group (H group; n=8), cardiopulmonary bypass (CPB) group (C group; n=24) and sevoflurane pre-conditioning group (S group; n=32). The C group was subjected to tracheal intubation and mechanical ventilation, vessel puncture and catheter placement in the right femoral artery and right internal jugular vein, while no CPB was performed in the H group. The S group was pre-treated with 2.4% sevoflurane for 1 h prior to establishing the CPB model. The CPB in the C and S groups was performed for 1 h. Blood of the rats was analyzed and clinical parameters were detected prior to, during and at various time-points after CPB. In addition, eight rats from the C and S groups each were sacrificed at these time-points and brain tissue samples were analyzed. The levels of the brain damage-specific protein S100-β as well as IL-6 and IFN-β in the serum were detected by ELISA; furthermore, the expression levels of TLR3 and TIR-domain-containing adapter-inducing interferon-β (TRIF) in the left hippocampus were assessed by ELISA and/or western blot analysis. The right hippocampus was assessed for neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The mean arterial pressure, heart rate and hematocrit were significantly decreased following CPB (P<0.05), while there was no significant changes in any other clinical parameters. The serum levels of S100-β and IL-6 in the C group were significantly increased compared with those in the H group (P<0.05), which was attenuated by sevoflurane-pre-treatment. Compared with the H group, the serum levels of IFN-β as well as hippocampal protein levels of TLR3 and TRIF were significantly increased in the C group during and after CPB (P<0.05), which was markedly aggravated in the S group (P<0.05). The number of apoptotic hippocampal neurons, although being generally low, was significantly increased in the C group compared with that in the H group (P<0.05), while apoptosis was significantly attenuated by sevoflurane-pre-treatment (P<0.05). The present study therefore concluded that 2.4% sevoflurane pre-treatment has a protective effect on the rat brain against CPB-induced injury, which may be mediated via the TLR3 signaling pathway through upregulating the expression levels of anti-inflammatory and downregulating pro-inflammatory proteins.

Eupatorium makinoi suppresses toll-like receptor signaling pathways

ABSTRACTToll-like receptors (TLRs) recognize microbial molecules that are widely presented by pathogens and initiate the innate immune system. TLR signaling is divided into two different signaling pathways, the myeloid differential factor 88 (MyD88)- and Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways. Eupatorium makinoi, a plant species in Asteraceae, is used for medicinal purposes in China, Korea, and Japan. Through our previous research, we found that an ethanol extract of E. makinoi (EEM) suppresses inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. In this study, we investigated the effect of EEM on TLRs signaling pathways. EEM suppresses NF-κB activation and iNOS and COX-2 expressions induced by TLR2 or TLR4 agonists. Also, EEM suppresses the activation of interferon (IFNs) regulatory factor 3 (IRF3) induced by TLR3 or TLR4 agonists. All results indicate that EEM suppresses myeloid differentiation primary-response protein 88 (MyD88) and TRIF-dependent signaling pathways of TLRs and the expressions of target genes derived from the activation of TLRs

Paying the Toll for Glucose Regulation: A Central Role for TLR3.

Innate immunity is now known to impact tissue metabolic responses with members of the Toll-like receptor 2 and 4 (TLR 2/4) family implicated in dyslipidemia. However, the impact of other TLR proteins on metabolic regulation has remained poorly understood. In this issue of Diabetes , Strodthoff et al. (1) provide interesting new evidence that TLR3 regulates glucose metabolism though the modulation of insulin levels in both rodents and humans. These findings reveal a new area of investigation in regulating glucose metabolism beyond fatty acid modulation of TLR 2/4 that may have the potential to reveal novel therapeutic targets. TLRs are critical to the regulation of innate immune responses. TLRs are transmembrane proteins that contain leucine-rich repeat domains capable of binding to conserved pathogen-associated molecular patterns (PAMPs). The PAMPS are comprised of bacterial, parasitic, or viral components, and the binding of these PAMPS to the extracellular domain of TLRs results in the activation of intracellular adaptor molecules. The two most common and studied downstream molecular adaptors are the myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF). Almost all identified TLRs signal through MyD88 except for TLR3. In contrast, only TLR3 and TLR4 signal via TRIF (2). The activation of MyD88 and TRIF results in a signaling cascade that leads to the formation of proinflammatory mediators. TLR3 is able to …

The involvement of the Toll-like receptor signaling and Nrf2-Keap1 pathways in the in vitro regulation of IL-8 and HMOX1 for skin sensitization

In vitro gene profiling studies have associated the molecular pathways of Nrf2-Keap1 and Toll-like receptor (TLR) signaling with skin sensitization. In this study, the role of these pathways in the regulation of protein biomarkers for skin sensitization was further elucidated using transient gene knock-down of key components of the signaling cascades in HaCaT cells after exposure to dinitrochlorobenzene (DNCB). The effect of targeting these pathways was established through evaluation of heme oxygenase1 (HMOX1) and interleukin (IL)-8 production. These experiments showed that Nrf2 is not involved in regulating HMOX1 after exposure to DNCB, but that activation of TLR signaling moderates the expression of HMOX1. The regulation of IL-8 depended on Nrf2, but also on the Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF) adaptor protein in TLR signaling. This study provides new insights into the regulation of HMOX1 and IL-8, but the exact regulating mechanisms remain to be further elucidated.

Hyaluronan ameliorates LPS-induced acute lung injury in mice via Toll-like receptor (TLR) 4-dependent signaling pathways

Toll-like receptor-4 (TLR4) signaling has been implicated in innate immunity and acute inflammation following acute lung injury (ALI). As such, modulating inflammatory response through TLR4 represents an attractive therapeutic approach to treat ALI. Increasing evidence demonstrates that hyaluronan (HA) can modulate TLR4 activation and has shown early promise as a therapeutic agent in ALI. However, the mechanism associated with HA has not been fully elucidated. In the current study, we sought to determine the effects of HA on lipopolysaccharide (LPS)-induced inflammatory response and gain insights into the mechanism of action in mice with intratracheal instillation of LPS. Our results demonstrate that in contrast to mice challenged with LPS, pretreatment with HA significantly inhibited inflammatory cell recruitment, attenuated lung injury and suppressed the level of cytokine/chemokine in bronchial alveolar lavage fluid (BALF). Investigation of the mechanism responsible for inhibition of LPS activation showed HA treatment significantly inhibited the nuclear translocation of NF-κB p65 and protein expression of myeloid differentiation primary response protein (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) and p38 MAPK, JNK and ERK activation in lung tissue. Furthermore, we compared the protection effect of HA in TLR4-deficient mice with those of genetically matched wild type (WT) mice in an acute model of lung injury. However, in TLR4-deficient mice, HA pretreatment before LPS instillation fail to affect the LPS response. Therefore, our findings suggest that HA pretreatment attenuated LPS-induced ALI and the anti-inflammatory function of HA was partial dependent on TLR4, which shed new light on potential elements that regulate the lung injury response.

Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation.

Nuclear factor of activated T-cells (NFAT) family transcription factors are known to undergo nuclear translocation in response to inflammatory stimulation. In this study, we uncovered a surprise transportation of NFATs into mitochondria in microglia after a prolonged treatment with bacteria endotoxin lipopolysaccharides (LPSs). LPSs activated Toll-like receptor 4 and its downstream Toll/interleukin 1 receptor-domain-containing adapter-inducing interferon-β (TRIF) to regulate the mitochondrial translocation of NFAT in microglia, whereas genetic inhibition of NFAT1 compromised TRIF-mediated cytokine production and reduced ATP and reactive oxygen species generation. These findings reveal a previously undescribed mitochondrial translocation of NFAT in microglia responding to extended activation of Toll-like receptor-mediated signaling transduction pathways.

Efficacy of atorvastatin on hippocampal neuronal damage caused by chronic intermittent hypoxia: Involving TLR4 and its downstream signaling pathway

Hippocampal neuronal damage is critical for the initiation and progression of neurocognitive impairment accompanied obstructive sleep apnea syndrome (OSAS). Toll-like receptor 4 (TLR4) plays an important role in the development of several hippocampus-related neural disorders. Atorvastatin was reported beneficially regulates TLR4. Here, we examined the effects of atorvastatin on hippocampal injury caused by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological change of OSAS.Mice were exposed to intermittent hypoxia with or without atorvastatin for 4 weeks. Cell damage, the expressions of TLR4 and its two downstream factors myeloid differentiation factor 88 (MYD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF), inflammatory agents (tumor necrosis factor α and interleukin 1β), and the oxidative stress (superoxide dismutase and malondialdehyde) were determined.Atorvastatin decreased the neural injury and the elevation of TLR4, MyD88, TRIF, pro-inflammatory cytokines and oxidative stress caused by CIH.Our study suggests that atorvastatin may attenuate CIH induced hippocampal neuronal damage partially via TLR4 and its downstream signaling pathway.

Liver X receptors contribute to periodontal pathogen‐elicited inflammation and oral bone loss

Periodontal diseases are chronic oral inflammatory diseases that are polymicrobial in nature. The presence of specific bacteria in subgingival plaque such as Porphyromonas gingivalis is associated with microbial dysbiosis and the modulation of host immune response. Bacterially elicited innate immune activation and inflammation are key elements implicated in the destruction of soft and hard tissues supporting the teeth. Liver X receptors (LXRs) are nuclear hormone receptors with important function in lipid homeostasis, inflammation, and host response to infection; however, their contribution to chronic inflammatory diseases such as periodontal disease is not understood. The aim of this study was to define the contribution of LXRs in the development of immune response to P. gingivalis and to assess the roles that LXRs play in infection-elicited oral bone loss. Employing macrophages, we observed that P. gingivalis challenge led to reduced LXRα and LXRβ gene expression compared with that observed with unchallenged wild-type cells. Myeloid differentiation primary response gene 88 (MyD88)-independent, Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling affected P. gingivalis-mediated reduction in LXRα expression, whereas neither pathway influenced the P. gingivalis effect on LXRβ expression. Employing LXR agonist and mice deficient in LXRs, we observed functional effects of LXRs in the development of a P. gingivalis-elicited cytokine response at the level of the macrophage, and participation of LXRs in P. gingivalis-elicited oral bone loss. These findings identify novel importance for LXRs in the pathogenesis of P. gingivalis infection-elicited inflammation and oral bone loss.

Suppression of the TRIF-dependent signaling pathway of Toll-like receptor by CDr10b in RAW264.7 macrophages.

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. TLR signaling pathways can be largely classified as either myeloid differential factor 88 (MyD88)- or toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways. Compound of Designation red 10 binding (CDr10b) was synthesized to investigate its role in neuroinflammatory diseases. This study was conducted to determine whether CDr10b can affect TLR signaling pathways. CDr10b suppressed NF-κB activation as well as COX-2 and iNOS expression induced by TLR3 or TLR4 agonists. CDr10b also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. These results indicate that CDr10b can modulate the TRIF-dependent pathway of TLRs and has the potential to become a new therapeutic drug for chronic inflammatory diseases.

32 TIR-Domain Containing Adapter-Inducing Interferon-β (TRIF) Promotes Early Phagocytosis in Response to Gram-Negative Enteropathogens

32 TIR-Domain Containing Adapter-Inducing Interferon-β (TRIF) Promotes Early Phagocytosis in Response to Gram-Negative Enteropathogens

Anti-inflammatory effect of Streptochlorin via TRIF-dependent signaling pathways in cellular and mouse models.

Streptochlorin, a small compound derived from marine actinomycete, has been shown to have anti-angiogenic, anti-tumor, and anti-allergic activities. However, the anti-inflammatory effects and underlying mechanisms have not yet been reported. In the present study, we investigated the effect of streptochlorin on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Streptochlorin attenuated the production of proinflammatory mediators such as nitric oxide, cyclooxygenase-2, pro-interleukin (IL)-1β, and IL-6 in LPS-stimulated RAW264.7 cells through inhibition of the Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling pathway. Furthermore, streptochlorin suppressed the infiltration of immune cells such as neutrophils into the lung and proinflammatory cytokine production such as IL-6 and TNF-α in broncho-alveolar lavage fluid (BALF) in the LPS-induced acute lung injury (ALI) mouse model. Streptochlorin has potent anti-inflammatory effects through regulating TRIF-dependent signaling pathways, suggesting that streptochlorin may provide a valuable therapeutic strategy in treating various inflammatory diseases.

CD14, TLR4 and TRAM Show Different Trafficking Dynamics During LPS Stimulation.

Toll-like receptor 4 (TLR4) is responsible for the immediate response to Gram-negative bacteria and signals via two main pathways by recruitment of distinct pairs of adaptor proteins. Mal-MyD88 [Mal (MyD88-adaptor-like) - MYD88 (Myeloid differentiation primary response gene (88))] is recruited to the plasma membrane to initiate the signaling cascade leading to production of pro-inflammatory cytokines while TRAM-TRIF [TRAM (TRIF-related adaptor molecule)-TRIF (TIR-domain-containing adapter-inducing interferon-β)] is recruited to early endosomes to initiate the subsequent production of type I interferons. We have investigated the dynamics of TLR4 and TRAM during lipopolysaccharide (LPS) stimulation. We found that LPS induced a CD14-dependent immobile fraction of TLR4 in the plasma membrane. Total internal reflection fluorescence microscopy (TIRF) revealed that LPS stimulation induced clustering of TLR4 into small punctate structures in the plasma membrane containing CD14/LPS and clathrin, both in HEK293 cells and the macrophage model cell line U373-CD14. These results suggest that laterally immobilized TLR4 receptor complexes are being formed and prepared for endocytosis. RAB11A was found to be involved in localizing TRAM to the endocytic recycling compartment (ERC) and to early sorting endosomes. Moreover, CD14/LPS but not TRAM was immobilized on RAB11A-positive endosomes, which indicates that TRAM and CD14/LPS can independently be recruited to endosomes.

TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice

ObjectiveThe gut microbiota modulates host susceptibility to intestinal inflammation, but the cell types and the signalling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here, we investigated...

A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases.