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Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model.

ABSTRACT: Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system and appear as a severity index of the clinical course.A total of 72 C57BL/6J mice, aged 12-14 weeks, were studied. The animals were divided into 3 sepsis (S) groups (24h, 48h and 72h) and 3 control (C) groups (24h, 48h and 72h), each consisting of 12 mice. The S-groups were subjected to cecal ligation and puncture (CLP) while the C-groups had a sham operation performed. Blood samples were drawn from all groups. Total blood count analysis was performed along with the measurement of certain biochemical markers. Additionally, lung tissues were harvested and the expression of TLRs, namely TLR 2, TLR 3, TLR 4 and TLR 7 were evaluated by means of immunofluorescence (IF) and qRT-PCR (quantitative-Polymerase Chain Reaction). Statistical analysis was performed by using one-way ANOVA followed by student t-test. Results were considered statistically significant when p<0.05.WBCs and lymphocytes were decreased in all S-groups compared to the corresponding C-groups (p<0.05), while RBCs showed a gradual decline in S-groups with the lowest levels appearing in the S72 group. Only, monocytes were higher in S-groups, especially between S48-C48 (p<0.05) and S72-C72 (p<0.05). Creatinine, IL-10 and IL-6 levels were significantly increased in the S-groups compared to the corresponding C-groups (S24 vs C24, S48 vs C48 and S72 vs C72, p<0.05). IF showed that expression of TLRs 2, 3, 4 and 7 was increased in all S-groups compared to the time-adjusted C-groups (p<0.05). Similarly, qRT-PCR revealed that expression of all TLRs was higher in all S-groups compared to their respective C-groups in both lungs and intestine (p<0.05). Comparing lung and intestinal tissues from S-groups, TLRs 2 and 4 were found increased in the lung at 24, 48 and 72 hours (p<0.05), whereas TLR 3 was higher in the intestine at all time points examined (p<0.05). Finally, TLR 7 levels were significantly higher in the intestinal tissues at 24 hours (p<0.0001), while lungs predominated at 48 hours (p<0.0001).TLRs seem to be highly expressed in the lungs of septic mice, therefore suggesting a potential role in the pathogenesis of ARDS during sepsis. While more studies need to be conducted in order to completely understand the underlying mechanisms, TLRs may represent a promising target for establishing novel therapeutic strategies in the treatment of sepsis.

SUBMITTER: Bakopoulos A

PROVIDER: S-EPMC5685586 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model.

Bakopoulos Anargyros A Kapelouzou Alkistis A Tsilimigras Diamantis I DI Katsimpoulas Michalis M Schizas Dimitrios D Aravanis Chrysostomos C Balafas Evaggelos E Mavroidis Manolis M Pavlakis Kitty K Machairas Anastasios A Liakakos Theodore T

PloS one 20171114 11

<h4>Background</h4>Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system ...[more]

PMID: 29136027

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Project description:BackgroundToll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis.MethodsThe expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data.ResultsOur multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research.ConclusionTLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Key MessagesToll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified.In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed.TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers.

Project description:Members of the family Suidae have diverged over extended evolutionary periods in diverse environments, suggesting that adaptation in response to endemic infectious agents may have occurred. Toll-like receptors (TLRs) comprise a multigene family that acts as the first line of defense against infectious microbes at the host-environment interface. We hypothesized that across the Suidae, positive selection mediated by infectious agents has contributed to the evolution of TLR diversity. Thus, we analyzed Sus scrofa, Sus barbatus, Sus verrucosus, Sus celebensis, Sus scebifrons, Babyrousa babyrussa, Potamochoerus larvatus, Potamochoerus porcus and Phacochoerus africanus genomes. Specifically, analyses were performed to identify evidence of positive selection using Maximum likelihood (ML) methods within a phylogenetic framework for bacterial and viral sensing Suidae TLR extracellular domains. Our analyses did not reveal evidence of positive selection for TLR3 and TLR7, suggesting strong functional conservation among these two genes for members of the Suidae. Positive selection was inferred for Suidae TLR1, TLR2, TLR6 and TLR8 evolution. ML methods identified amino acid sites of the bacterial sensing TLR1, TLR2, TLR6 and the viral sensing TLR8 to be under persistent positive selection. Some of these sites are in close proximity to functionally relevant sites, further strengthening the case for pathogen mediated selection for these sites. The branch leading to the genus Sus demonstrated evidence of episodic positive selection for TLR1, indicating selection mediated by infectious agents encountered within the specific geographic origin of the Sus. These results indicate that species of the Suidae have positively selected residues within functional domains of TLRs reflective of prior infections. Thus, TLR genes represent candidates for experimental validation to determine their functional role in antibacterial and antiviral activity within members of the Suidae.

Dataset Information

Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model.

Publications

Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model.

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