Triggering Receptors Expressed on Myeloid Cells 2 Promotes Corneal Resistance Against Pseudomonas aeruginosa by Inhibiting Caspase-1-Dependent Pyroptosis

Qu, Wenting; Wang, Yi; Wu, Yongjian; Liu, Yiting; Chen, Kang; Liu, Xi; Zou, Zhengyu; Huang, Xi; Wu, Minhao

doi:10.3389/fimmu.2018.01121

Cited by 36 publications

(33 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, activation of microglial CR1 induces neurotoxic cytokines and reactive oxygen species (53). Although TREM2 is found to upregulate complement components during aging (69), it can inhibit inflammasome activation (67). CD33 may induce NLRP3 inflammasome assembly (48).…”

Section: Role Of Tlr4 Signaling In Alzheimer's Disease Brainmentioning

confidence: 99%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

View full text Add to dashboard Cite

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

show abstract

Section: Role Of Tlr4 Signaling In Alzheimer's Disease Brainmentioning

confidence: 99%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

View full text Add to dashboard Cite

show abstract

“…Similarly, knockout mice for Tyrobp , the other gene commonly associated with NHD encoding the adapter protein for TREM2, exhibits increased autoantibodies (e.g., anti-double stranded DNA) and IgG2a/3 levels, and defects of NK and T cells' regulatory function. Recently, Qu et al (15) found an increased production of pro-inflammatory cytokines (IL-1β, IL-18, and CXCL2) and overactivation of the NLRP3 inflammasome pathway in Trem2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Expansion in Nasu-Hakola Disease: Immunological Findings in Three Patients and Proposal of a Unifying Pathogenic Hypothesis

et al. 2019

View full text Add to dashboard Cite

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive presenile dementia and bone cysts, caused by variants in either TYROBP or TREM2 . Despite the well-researched role of TREM2 and TYROBP/DAP12 in immunity, immunological phenotypes have never been reported in NHD patients. We initially diagnosed an Italian patient, using whole exome sequencing, with classical NHD clinical sequelae who additionally showed a decrease in NK cells and autoimmunity features underlined by the presence of autoantibodies. Based on this finding, we retrospectively explored the immunophenotype in another two NHD patients, in whom a low NK cell count and positive autoantibody serology were recorded. Accordingly, Trem2 −/− mice show abnormal levels of circulating proinflammatory cytokines and the dysfunction of immune cells, whereas knockout mice for Tyrobp , encoding the adapter for TREM2, exhibit increased levels of autoantibodies and defective NK cell activity. Our findings tend to redefine NHD as a multisystem “immunological” disease, considering that osteoclasts are derived from the fusion of mononuclear myeloid precursors, whereas neurological anomalies in NHD are directly caused by microglia dysfunction.

show abstract

“…Pyroptosis is a type of proinflammatory programmed cell death, which may be involved in the early process of corneal resistance to infection and removal of P. aeruginosa as previous reported. 31 Exoproteins (including superantigens and cytolysins) induced proinflammatory signals from epithelial cells have been well characterized in Staphylococcus aureus infection. 32 The pathogenesis of P. aeruginosa at the corneal epithelial surface remains unclear.…”

Section: Discussionmentioning

confidence: 99%

The Role of Elastase in Corneal Epithelial Barrier Dysfunction Caused by Pseudomonas aeruginosa Exoproteins

Wang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE.To investigate the role of elastase in corneal epithelial barrier dysfunction caused by the exoproteins secreted by Pseudomonas aeruginosa. METHODS.Exoproteins obtained from Pseudomonas aeruginosa culture supernatant were analyzed by shotgun proteomics approach. In vitro multilayered rabbit corneal epithelial barrier model prepared by air-liquid interface technique (CECs-ALI) were treated with 2 μg/ml exoproteins and/or 8 mM elastase inhibitor. Then the epithelial barrier function was evaluated by transepithelial electrical resistance (TEER) assay and tight junction proteins immunofluorescence. Cell viability and the apoptosis rate were examined by CCK8 assay and flow cytometry. TNF-α, IL-6, IL-8, and IL-1β levels were measured by ELISA. Mice cornea treated with exoproteins and/or elastase inhibitor were evaluated in vivo and in vitro. RESULTS. Elastase (24.2%) is one of the major components of exoproteins. After 2 μg/ml exoproteins were applied to CECs-ALI for two hours, TEER decreased from 323.2 ± 2.7 to 104 ± 6.8 Ω/cm 2 (P < 0.001). The immunofluorescence results showed a distinct separation in tight junction and significant degradation of ZO-1 and occludin (P < 0.05). Elastase inhibitor (8 mM) alleviated the decrease in TEER value (234 ± 6.8 Ω cm 2 ) induced by exoproteins. Inhibition of elastase decreased the apoptosis rate of CECs treated with exoproteins from 30.2 ± 3.8% to 7.26 ± 1.3% and the levels of inflammatory factors (P < 0.05). Mice corneal epithelium defect could be induced by exoproteins and protected by elastase inhibitor. CONCLUSIONS.Elastase plays a critical role in corneal epithelial barrier dysfunction caused by Pseudomonas aeruginosa exoproteins via damaging tight junctions. The inhibition of elastase could protect the corneal epithelial barrier via reducing virulence and inflammation.

show abstract

Triggering Receptors Expressed on Myeloid Cells 2 Promotes Corneal Resistance Against Pseudomonas aeruginosa by Inhibiting Caspase-1-Dependent Pyroptosis

Cited by 36 publications

References 46 publications

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

Phenotypic Expansion in Nasu-Hakola Disease: Immunological Findings in Three Patients and Proposal of a Unifying Pathogenic Hypothesis

The Role of Elastase in Corneal Epithelial Barrier Dysfunction Caused by Pseudomonas aeruginosa Exoproteins

Contact Info

Product

Resources

About