Caspases are key regulators of inflammatory and innate immune responses mediated by TLR3 in vivo

Shaalan, Abeer; Carpenter, Guy; Proctor, Gordon

doi:10.1016/j.molimm.2017.12.018

“…Recent studies propose a close association of inflammation and cell death [21, 22]. Induction of cell death in HBMEC is a mechanism some pathogens employ, presumably to gain entrance into the CNS by an impairment of BBB integrity [23–27].…”

Section: Introductionmentioning

confidence: 99%

More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells

Silwedel¹,

Haarmann

²

,

Fehrholz³

et al. 2019

J Neuroinflammation

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Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma -driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma ( U. ) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death ( p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 ( p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure ( p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 ( p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp. Electronic supplementary material The online version of this article (10.1186/s12974-019-1413-8) contains supplementary material, which is available to authorized users.

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“…Inflammation is classically understood to be initiated by early pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 [23]. However, recent studies have suggested an interlinkage of apoptosis and inflammation, proposing a crucial role for caspases in both [24, 25]. Whereas caspases 3, 8, and 9 are among those primarily involved in apoptosis, caspases 4 and 5 mediate inflammatory responses and pyroptosis as an inflammatory form of cell death [26, 27].…”

Section: Introductionmentioning

confidence: 99%

Differential modulation of pulmonary caspases: Is this the key to Ureaplasma-driven chronic inflammation?

Silwedel¹,

Fehrholz²,

Speer³

et al. 2019

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Although accepted agents in chorioamnionitis and preterm birth, the role of Ureaplasma species (spp.) in inflammation-driven morbidities of prematurity, including the development of bronchopulmonary dysplasia, remains controversial. To add to scarce in vitro data addressing the pro-inflammatory capacity of Ureaplasma spp., pulmonary epithelial-like A549 cells and human pulmonary microvascular endothelial cells (HPMEC) were incubated with Ureaplasma (U . ) urealyticum , U . parvum , and Escherichia coli lipopolysaccharide (LPS). Ureaplasma isolates down-regulated caspase mRNA levels in A549 cells (caspase 8: p <0.001, 9: p <0.001, vs. broth), while increasing caspase protein expression, enzyme activity, and cell death in HPMEC (active caspase 3: p <0.05, caspase 8: p <0.05, active caspase 9: p <0.05, viability: p <0.05). LPS, contrarily, induced caspase mRNA expression in HPMEC (caspase 3: p <0.01, 4: p <0.001, 5: p <0.001, 8: p <0.001, vs. control), but not in A549 cells, and did not affect enzyme activity or protein levels in either cell line. LPS, but neither Ureaplasma isolate, enhanced mRNA expression of pro-inflammatory interleukin ( IL)-6 in both A549 ( p <0.05, vs. control) and HPMEC ( p <0.001) as well as tumor necrosis factor-α ( p <0.01), IL-1β ( p <0.001), and IL-8 ( p <0.05) in HPMEC. We are therefore the first to demonstrate a differential modulation of pulmonary caspases by Ureaplasma spp. in vitro . Ureaplasma -driven enhanced protein expression and activity of caspases in pulmonary endothelial cells result in cell death and may cause structural damage. Down-regulated caspase mRNA in pulmonary epithelial cells, contrarily, may indicate Ureaplasma -induced inhibition of apoptosis and prevent effective immune responses. Both may ultimately contribute to chronic Ureaplasma colonization and long-term pulmonary inflammation.

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“…The present study identified a total of 11 coexpressed mRNAs. IL1B ( 46 ), SP100 Nuclear Antigen ( 47 ), FAS ( 48 ) and TLR3( 49 ) are mRNAs that are regulators that modulate the inflammatory and immune responses. The possibility that linc-LPA-1 serves a role in the inflammatory and immune responses in MFS by regulating mRNA expression levels requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of long non‑coding RNA expression profiles in Marfan syndrome

Gu

¹

,

Ni

²

,

Sheng

³

et al. 2020

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Long non-coding RNAs (lncRNAs) serve a crucial role in every aspect of cell biological functions as well as in a variety of diseases, including cardiovascular disease, cancer and nervous system disease. However, the differential expression profiles of lncRNAs in Marfan syndrome (MFS) have not been reported. The aim of the present study was to identify potential target genes behind the pathogenesis of MFS by analyzing microarray profiles of lncRNA in aortic tissues from individuals with MFS and normal aortas (NA). The differentially expressed lncRNA profiles between MFS (n=3) and NA (n=4) tissues were analyzed using microarrays. Bioinformatics analyses were used to further investigate the candidate lncRNAs. Reverse transcription-quantitative (RT-qPCR) was applied to validate the results. In total, the present study identified 294 lncRNAs (245 upregulated and 49 downregulated) and 644 mRNAs (455 upregulated and 189 downregulated) which were differential expressed between MFS and NA tissues (fold change ≥1.5; P<0.05). Gene Ontology enrichment analysis indicated that the differentially expressed mRNAs were involved in cell adhesion, elastic fiber assembly, extracellular matrix (ECM) organization, the response to virus and the inflammatory response. Kyoto Encyclopedia of Gene and Genomes pathway analysis indicated that the differentially expressed mRNAs were mainly associated with focal adhesion, the ECM-receptor interaction, the mitogen-activated protein kinase signaling pathway and the tumor necrosis factor signaling pathway. The lncRNA-mRNA coexpression network analysis further elucidated the interaction between the lncRNAs and mRNAs. A total of five lncRNAs (uc003jka.1, uc003jox.1, X-inactive specific transcript, linc-lysophosphatidic acid receptor 1 and linc-peptidylprolyl isomerase domain and WD repeat containing 1) with the highest degree of coexpression were selected and confirmed using RT-qPCR. In the present study, expression profiles of lncRNA and mRNA in MFS were revealed using microarray analysis. These results provided novel candidates for further investigation of the molecular mechanisms and effective targeted therapies for MFS.

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Caspases are key regulators of inflammatory and innate immune responses mediated by TLR3 in vivo

Cited by 11 publications

References 52 publications

More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells

More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells

Differential modulation of pulmonary caspases: Is this the key to Ureaplasma-driven chronic inflammation?

Microarray analysis of long non‑coding RNA expression profiles in Marfan syndrome

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