Transcriptome analysis of inflammation-related gene expression in endothelial cells activated by complement MASP-1

Schwaner, Endre; Németh, Zsuzsanna; Jani, Péter K.; Kajdácsi, Erika; Debreczeni, Márta L.; Doleschall, Zoltán; Dobó, József; Gál, Péter; Rigó, János; András, Kinga; Hegedüs, Tamás; Cervenak, László

doi:10.1038/s41598-017-09058-8

Cited by 17 publications

(18 citation statements)

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“…Moreover, MASP-1 treatment increased adhesion between neutrophils and endothelial cells by upregulating E-selectin expression in human umbilical vein endothelial cells (HUVECs) ( 98 ). A genome-wide gene expression profiling study on HUVECs corroborated the role of MASP-1 in triggering inflammation ( 99 ). The analysis showed that MASP-1 up- and downregulated numerous inflammation-related genes bridging complement activation and endothelial-cell-related inflammatory processes.…”

Section: Components Of Ap and Lp As Potential Drug Targetsmentioning

confidence: 85%

Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases

2018

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The complement system has moved into the focus of drug development efforts in the last decade, since its inappropriate or uncontrolled activation has been recognized in many diseases. Some of them are primarily complement-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, and atypical hemolytic uremic syndrome. Complement also plays a role in various multifactorial diseases that affect millions of people worldwide, such as ischemia reperfusion injury (myocardial infarction, stroke), age-related macular degeneration, and several neurodegenerative disorders. In this review, we summarize the potential advantages of targeting various complement proteins with special emphasis on the components of the lectin (LP) and the alternative pathways (AP). The serine proteases (MASP-1/2/3, factor D, factor B), which are responsible for the activation of the cascade, are straightforward targets of inhibition, but the pattern recognition molecules (mannose-binding lectin, other collectins, and ficolins), the regulatory components (factor H, factor I, properdin), and C3 are also subjects of drug development. Recent discoveries about cross-talks between the LP and AP offer new approaches for clinical intervention. Mannan-binding lectin-associated serine proteases (MASPs) are not just responsible for LP activation, but they are also indispensable for efficient AP activation. Activated MASP-3 has recently been shown to be the enzyme that continuously supplies factor D (FD) for the AP by cleaving pro-factor D (pro-FD). In this aspect, MASP-3 emerges as a novel feasible target for the regulation of AP activity. MASP-1 was shown to be required for AP activity on various surfaces, first of all on LPS of Gram-negative bacteria.

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Section: Components Of Ap and Lp As Potential Drug Targetsmentioning

confidence: 85%

Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases

2018

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“…We have recently reported that in ECs, rMASP-1 regulates the expression of genes involved in the inflammatory reaction (29). Here we show that rMASP-1 treatment significantly changed the expression of 25 permeability-related genes.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA isolation and microarray processing were carried out as described in our earlier study (29). Briefly, confluent layers of HUVECs from four individuals were cultured in 6-well plates and treated for 2 h with 0.6 μM rMASP-1.…”

Section: Methodsmentioning

confidence: 99%

MASP-1 Increases Endothelial Permeability

et al. 2019

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Pathologically increased vascular permeability is an important dysfunction in the pathomechanism of life-threatening conditions, such as sepsis, ischemia/reperfusion, or hereditary angioedema (HAE), diseases accompanied by uncontrolled activation of the complement system. HAE for example is caused by the deficiency of C1-inhibitor (the main regulator of early complement activation), which leads to edematous attacks threatening with circulatory collapse. We have previously reported that endothelial cells become activated during HAE attacks. A natural target of C1-inhibitor is mannan-binding lectin-associated serine protease-1 (MASP-1), a multifunctional serine protease, which plays a key role in the activation of complement lectin pathway. We have previously shown that MASP-1 induces the pro-inflammatory activation of endothelial cells and in this study we investigated whether MASP-1 can directly affect endothelial permeability. All experiments were performed on human umbilical vein endothelial cells (HUVECs). Real-time micro electric sensing revealed that MASP-1 decreases the impedance of HUVEC monolayers and in a recently developed permeability test (XperT), MASP-1 dose-dependently increased endothelial paracellular transport. We show that protease activated receptor-1 mediated intracellular Ca 2+ -mobilization, Rho-kinase activation dependent myosin light chain (MLC) phosphorylation, cytoskeletal actin rearrangement, and disruption of interendothelial junctions are underlying this phenomenon. Furthermore, in a whole-transcriptome microarray analysis MASP-1 significantly changed the expression of 25 permeability-related genes in HUVECs—for example it up-regulated bradykinin B2 receptor expression. According to our results, MASP-1 has potent permeability increasing effects. During infections or injuries MASP-1 may help eliminate the microbes and/or tissue debris by enhancing the extravasation of soluble and cellular components of the immune system, however, it may also play a role in the pathomechanism of diseases, where edema formation and complement lectin pathway activation are simultaneously present. Our findings also raise the possibility that MASP-1 may be a promising target of anti-edema drug development.

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“…This activity (like that of kallikrein) enables the release of bradykinin, a highly pro-inflammatory mediator of the contact system. Furthermore, it was demonstrated that MASP-1 contributes to the pro-inflammatory activation of endothelial cells and increases endothelial permeability [ 82 , 83 , 84 ]. Recently, MASP-1 was reported to affect the transcription of alternative pathway factor D [ 85 ].…”

Section: Mbl-associated Serine Proteases (Masp) and Their Related mentioning

confidence: 99%

Components of the Lectin Pathway of Complement in Haematologic Malignancies

Cedzyński

Świerzko

2020

Cancers

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The complement system is activated cascadically via three distinct major routes: classical pathway (CP), alternative pathway (AP) or lectin pathway (LP). The unique factors associated with the latter are collectins (mannose-binding lectin, collectin-10, collectin-11), ficolins (ficolin-1, ficolin-2, ficolin-3) and proteins of the mannose-binding lectin-associated serine protease (MASP) family (MASP-1, MASP-2, MASP-3, MAp19, MAp44). Collectins and ficolins are both pattern-recognising molecules (PRM), reactive against pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP). The MASP family proteins were first discovered as complexes with mannose-binding lectin (MBL) and therefore named MBL-associated serine proteases, but later, they were found to interact with ficolins, and later still, collectin-10 and collectin-11. As well as proteolytic enzymes (MASP-1, MASP-2, MASP-3), the group includes non-enzymatic factors (MAp19, MAp44). In this review, the association-specific factors of the lectin pathway with haematologic malignancies and related infections are discussed.

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Transcriptome analysis of inflammation-related gene expression in endothelial cells activated by complement MASP-1

Cited by 17 publications

References 50 publications

Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases

Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases

MASP-1 Increases Endothelial Permeability

Components of the Lectin Pathway of Complement in Haematologic Malignancies

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