Search

Background: Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD. Method: This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched. Results: Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890_C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53–0.99). Furthermore, a stratified analysis revealed that rs5743890_C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p < 0.00001, OR = 1.48, 95% CI = 1.33–1.65) and rs3750920 T (p < 0.00001, OR = 1.34, 95% CI = 1.26–1.44). The survival of IPF patients was correlated with the TOLLIP rs5743890 SNP, and patients with the rs5743890_C genotype had worse survival (p = 0.02, HR = 1.59, 95% CI = 1.07–2.36). Conclusion: This study showed that rs5743890_C was associated with a lower incidence of ILD and a worse survival rate in patients with IPF. Rs111521887_G and rs3750920_T were found to be associated with an elevated risk of ILD incidence, while no significant association was observed with ILD prognosis. Furthermore, studies are warranted to validate our results and assess the effects of TOLLIP genetic variants on ILD. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD. Method This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched. Results Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890_C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53–0.99). Furthermore, a stratified analysis revealed that rs5743890_C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p

Abstract Background Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated. Methods Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h. Results Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling. Conclusions Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.

Plasmodium vivax (Pv) accounts for over 50% of malaria cases in Latin America and Asia. Despite a significant reduction in Pv transmission in Thailand, the parasite remains endemic to the border areas. This study aimed to investigate the genetic diversity of the parasites and the host factors, as well as their relation to parasite density in Pvisolates, along the Thai–Myanmar border. Genetic variations in Pv markers, specifically the ookinete surface protein Pvs25, and host genes, including Toll-like receptor 6 (TLR6), TLR9, TIR Domain-containing adaptor protein (TIRAP), Toll-interacting protein (TOLLIP), Duffy antigen receptor for chemokines (DARC), and intercellular adhesion molecule 1 (ICAM-1), were investigated using polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP). A total of 548 PCR-positive Pv samples collected from Tak and Kanchanaburi provinces during two periods (2006–2007 and 2014–2016) were included in the study. Pvs25 exhibited four haplotypes, with H1 (EGTKV) being the most prevalent in both provinces. Kanchanaburi isolates exhibited greater genetic diversity than Tak isolates. No significant deviations from neutrality were observed for Pvs25 in either area. ICAM-1 and TOLLIP s3750920 heterozygous carriers had greater median parasite densities than homozygous mutants. The TLR9 rs187084 T genotype had a significantly higher parasite density than the non-T genotype. The findings underscore the significant association between the rs3750920 C/T, rs5498 A/G, and rs187084 T genotypes and high parasite density in patients infected with Pv, highlighting their potentially critical role in malaria susceptibility.

Plasmodium vivax (Pv) accounts for over 50% of malaria cases in Latin America and Asia. Despite a significant reduction in Pv transmission in Thailand, the parasite remains endemic to the border areas. This study aimed to investigate the genetic diversity of the parasites and the host factors, as well as their relation to parasite density in Pvisolates, along the Thai–Myanmar border. Genetic variations in Pv markers, specifically the ookinete surface protein Pvs25, and host genes, including Toll-like receptor 6 (TLR6), TLR9, TIR Domain-containing adaptor protein (TIRAP), Toll-interacting protein (TOLLIP), Duffy antigen receptor for chemokines (DARC), and intercellular adhesion molecule 1 (ICAM-1), were investigated using polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP). A total of 548 PCR-positive Pv samples collected from Tak and Kanchanaburi provinces during two periods (2006–2007 and 2014–2016) were included in the study. Pvs25 exhibited four haplotypes, with H1 (EGTKV) being the most prevalent in both provinces. Kanchanaburi isolates exhibited greater genetic diversity than Tak isolates. No significant deviations from neutrality were observed for Pvs25 in either area. ICAM-1 and TOLLIP s3750920 heterozygous carriers had greater median parasite densities than homozygous mutants. The TLR9 rs187084 T genotype had a significantly higher parasite density than the non-T genotype. The findings underscore the significant association between the rs3750920 C/T, rs5498 A/G, and rs187084 T genotypes and high parasite density in patients infected with Pv, highlighting their potentially critical role in malaria susceptibility. [ABSTRACT FROM AUTHOR]

Background: Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated. Methods: Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h. Results: Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling. Conclusions: Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection. [ABSTRACT FROM AUTHOR]

Variations in the Toll‐interacting protein (TOLLIP) gene have been identified in genome‐wide association studies to correlate with risk of disease, mortality, and response to N‐acetylcysteine therapy in idiopathic pulmonary fibrosis. Although TOLLIP is known to modulate innate immune responses, its relevance in organ fibrogenesis remains unknown. Prior work in the literature suggests TOLLIP dampens transforming growth factor beta (TGFβ) signaling in human cell lines. In this study, we examined the role of TOLLIP in mouse lung fibroblast (MLF) responses to TGFβ and in the bleomycin model of experimental lung fibrosis using Tollip−/− mice. We hypothesize that if TOLLIP negatively regulates TGFβ signaling, then Tollip−/− mouse lung fibroblasts (MLFs) would have enhanced response to TGFβ treatment, and Tollip−/− mice would develop increased fibrosis following bleomycin challenge. Primary MLFs were stimulated with TGFβ (1 ng/mL) for 24 h. RNA was obtained to assess global transcriptional responses by RNA‐seq and markers of myofibroblast transition by qPCR. Functional assessment of TGFβ‐stimulated MLFs included cell migration by scratch assay, cell proliferation, and matrix invasion through Matrigel. In the in vivo model of lung fibrosis, Tollip−/− mice and wild‐type (WT) littermates were administered bleomycin intratracheally and assessed for fibrosis. We further examined TGFβ signaling in vivo after bleomycin injury by SMAD2, ERK1/2, and TGFβR1 Western blot. In response to TGFβ treatment, both WT and Tollip−/− MLFs exhibited global transcriptional changes consistent with myofibroblast differentiation. However, Tollip−/− MLFs showed greater number of differentially expressed genes compared to WT MLFs and greater upregulation of Acta2 by qPCR. Functionally, Tollip−/− MLFs also exhibited increased migration and Matrigel invasiveness compared to WT. We found evidence of enhanced TGFβ signaling in Tollip−/− through SMAD2 in vitro and in vivo. Tollip−/− mice experienced lower survival using a standard weight‐adjusted dosing without evidence of differences in fibrosis at Day 21. With adjustment of dosing for sex, no differences were observed in fibrosis at Day 21. However, Tollip−/− mice had greater weight loss and increased bronchoalveolar lavage fluid total protein during early resolution at Day 14 compared to WT without evidence of differences in acute lung injury at Day 7, suggesting impaired resolution of lung injury. [ABSTRACT FROM AUTHOR]

Proteostasis of the endoplasmic reticulum (ER) is maintained by coordinated action of two major catabolic pathways: proteasome-dependent ER-associated degradation (ERAD) and less characterized lysosomal pathways. Recent studies on ER-specific autophagy (termed "reticulophagy") have highlighted the importance of lysosomes for ER proteostasis. Key to this process are proteins termed reticulophagy receptors that connect ER fragments and Atg8-family proteins, facilitating the lysosomal degradation of both native and aberrant ER proteins in a relatively nonselective manner. In contrast, our recent work identified TOLLIP as a novel type of cargo receptor specifically dedicated to the lysosomal degradation of aberrant ER membrane proteins. The clients of TOLLIP include an engineered model substrate, which mimics an ER-retained aberrant membrane protein, and motor neuron disease-linked misfolded mutants of VAPB and BSCL2/Seipin. TOLLIP acts as a receptor to connect these aberrant ER membrane proteins and phosphatidylinositol-3-phosphate (PtdIns3P) by recognizing the former through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain, and the latter through its C2 domain. These interactions enable PtdIns3P-dependent vesicular trafficking of aberrant membrane proteins to lysosomes without promoting reticulophagic turnover of bulk ER. [ABSTRACT FROM AUTHOR]

Target of Myb1 (TOM1) facilitates the transport of endosomal ubiquitinated proteins destined for lysosomal degradation; however, the mechanisms regulating TOM1 during this process remain unknown. Here, we identified an adjacent DXXLL motif-containing region to the TOM1 VHS domain, which enhances its affinity for ubiquitin and can be modulated by phosphorylation. TOM1 is an endosomal phosphatidylinositol 5-phosphate (PtdIns5P) effector under Shigella flexneri infection. We pinpointed a consensus PtdIns5P-binding motif in the VHS domain. We show that PtdIns5P binding by TOM1 is pH-dependent, similarly observed in its binding partner TOLLIP. Under acidic conditions, TOM1 retained its complex formation with TOLLIP, but was unable to bind ubiquitin. S. flexneri infection inhibits pH-dependent endosomal maturation, leading to reduced protein degradation. We propose a model wherein pumping of H+ to the cytosolic side of endosomes contributes to the accumulation of TOM1, and possibly TOLLIP, at these sites, thereby promoting PtdIns5P- and pH-dependent signaling, facilitating bacterial survival. [Display omitted] • Binding of TOM1 VHS to ubiquitin is enhanced by an internal DXXLL motif • Binding of TOM1 to PtdIns5P is maximal under acidic conditions • TOLLIP's binding to PtdIns5P also increases as pH acidifies • A tight TOM1-TOLLIP complex binds to PtdIns5P under acidic conditions Xiong and Roach et al. report a DXXLL motif in TOM1 that increases its affinity for ubiquitin binding. They identify a PtdIns5P-binding site in TOM1 and demonstrate that its binding is maximal under acidic conditions. Furthermore, under these conditions, the TOM1-TOLLIP complex also interacts with the phosphoinositide. [ABSTRACT FROM AUTHOR]

Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes. 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO 2) and particulate matter ≤10 μm in aerodynamic diameter (PM 10) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro , cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid. Significant interaction was observed between modelled air pollution (weekly NO 2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO 2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation. Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution. [Display omitted] • SNPs in the MUC5B and TOLLIP regions modify infants' susceptibility to NO2. • This may help identify infants more susceptible to air pollution effects on the lungs. • Downregulation of TOLLIP alters cell reactions to pollutants (in vitro analysis). [ABSTRACT FROM AUTHOR]

Toll-interacting protein (Tollip) serves as a crucial inhibitory factor in the modulation of Toll-like receptor (TLR)-mediated innate immunological responses. The structure and function of Tollip have been well documented in mammals, yet the information in teleost remained limited. This work employed in vitro overexpression and RNA interference in vivo and in vitro to comprehensively examine the regulatory effects of Aj Tollip on NF-κB and MAPK signaling pathways. The levels of p65, c-Fos, c-Jun, IL-1, IL-6, and TNF-α were dramatically reduced following overexpression of Aj Tollip, whereas knocking down Aj Tollip in vivo and in vitro enhanced those genes' expression. Protein molecular docking simulations showed Aj Tollip interacts with Aj TLR2, Aj IRAK4a, and Aj IRAK4b. A better understanding of the transcriptional regulation of Aj Tollip is crucial to elucidating the role of Tollip in fish antibacterial response. Herein, we cloned and characterized a 2.2 kb Aj Tollip gene promoter sequence. The transcription factors GATA1 and Sp1 were determined to be associated with the activation of Aj Tollip expression by using promoter truncation and targeted mutagenesis techniques. Collectively, our results indicate that Aj Tollip suppresses the NF-κB and MAPK signaling pathways, leading to the decreased expression of the downstream inflammatory factors, and GATA1 and Sp1 play a vital role in regulating Aj Tollip expression. • Aj Tollip modulates the host immune response by inhibiting NF-κB or MAPK signaling pathways. • The transcription factors GATA1 and Sp1 play essential roles in the transcription of Aj Tollip. • Aj Tollip shows strong interaction with Aj TLR2 and Aj IRAK4. [ABSTRACT FROM AUTHOR]

Background: Pathophysiology of levodopa-induced dyskinesia (LID) remains obscure. Increased dopamine metabolism due to prolonged levodopa treatment can exacerbate oxidative damage and neuroinflammatory pathology in Parkinson's disease (PD). Association of novel peripheral markers with LID severity might provide insight into LID pathomechanisms., Objective: We aimed to study specific peripheral blood inflammatory-oxidative markers in LID patients and investigate their association with clinical severity of LID., Method: Motor, non-motor and cognitive changes in PD with and without LID compared to healthy-matched controls were identified. Within the same cohort, inflammatory marker (sLAG3, TOLLIP, NLRP3 and IL-1β) levels and antioxidant enzyme activities were determined by ELISA and spectrophotometric methods., Results: LID patients showed distinctly upregulated TOLLIP, IL-1β levels with significant diminution of antioxidant activity compared to controls. Significant negative association of cognitive markers with oxidative changes was also observed., Conclusion: To our understanding, this is the first study that indicates the involvement of toll-like receptor-mediated distinct and low-grade inflammatory activation in LID pathophysiology.