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Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts.

ABSTRACT: Introduction: Cardiac fibroblasts (CF) are crucial cells in damaged heart tissues, expressing TLR4, IFN-receptor and responding to lipopolysaccharide (LPS) and interferon-β (IFN-β) respectively. While CF interact with immune cells; however, their relationship with neutrophils remains understudied. Additionally, theimpact of LPS and IFN-β on CF-neutrophil interaction is poorly understood. Methods: Isolated CF from adult rats were treated with LPS, with or without IFN-β. This study examined IL-8 secretion, ICAM-1 and VCAM-1 expression, and neutrophil recruitment, as well as their effects on MMPs activity. Results: LPS triggered increased IL-8 expression and secretion, along with elevated ICAM-1 and VCAM-1 expression, all of which were blocked by TAK-242. Pre-treatment with IFN-β countered these LPS effects. LPS treated CF showed higher neutrophil recruitment (migration and adhesion) compared to unstimulated CF, an effect prevented by IFN-β. Ruxolitinib blocked these IFN-β anti-inflammatory effects, implicating JAK signaling. Analysis of culture medium zymograms from CF alone, and CF-neutrophils interaction, revealed that MMP2 was mainly originated from CF, while MMP9 could come from neutrophils. LPS and IFN-β boosted MMP2 secretion by CF. MMP9 activity in CF was low, and LPS or IFN-β had no significant impact. Pre-treating CF with LPS, IFN-β, or both before co-culture with neutrophils increased MMP2. Neutrophil co-culture increased MMP9 activity, with IFN-β pre-treatment reducing MMP9 compared to unstimulated CF. Conclusion: In CF, LPS induces the secretion of IL-8 favoring neutrophils recruitment and these effects were blocked by IFN-. The results highlight that CF-neutrophil interaction appears to influence the extracellular matrix through MMPs activity modulation.

SUBMITTER: Anfossi R

PROVIDER: S-EPMC10547890 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts.

Anfossi Renatto R Vivar Raúl R Ayala Pedro P González-Herrera Fabiola F Espinoza-Pérez Claudio C Osorio José Miguel JM Román-Torres Mauricio M Bolívar Samir S Díaz-Araya Guillermo G

Frontiers in cell and developmental biology 20230920

<b>Introduction:</b> Cardiac fibroblasts (CF) are crucial cells in damaged heart tissues, expressing TLR4, IFN-receptor and responding to lipopolysaccharide (LPS) and interferon-β (IFN-β) respectively. While CF interact with immune cells; however, their relationship with neutrophils remains understudied. Additionally, theimpact of LPS and IFN-β on CF-neutrophil interaction is poorly understood. <b>Methods:</b> Isolated CF from adult rats were treated with LPS, with or without IFN-β. This study e ...[more]

PMID: 37799272

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Project description:ObjectivesAcute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini. Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear.MethodsThis study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo. The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern.ResultsEsculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with β2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1).ConclusionsEsculin inhibits β2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive.MethodsTo evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients.ResultsIn the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival.ConclusionsOur study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC.

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Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts.

Publications

Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts.

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