Elevated plasma interleukin 34 levels correlate with disease severity-reflecting parameters of patients with haemorrhagic fever with renal syndrome

Kang, Tae‐Young; Zhang, Chunmei; Zhang, Yusi; Du, Hongwu; Jin, Boquan; Ma, Ying

doi:10.1080/23744235.2019.1672887

Cited by 12 publications

(6 citation statements)

References 43 publications

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“…Since portal blood from healthy individuals is not accessible without invasive intervention, portal blood control samples could not be ethically obtained for comparison. Therefore, portal and peripheral blood samples were compared to manufacturer/literature cited mean or median values for healthy human peripheral blood plasma (mean 33.7pg/ml GM-CSF, BioLegend, mean 83.7pg/ml M-CSF, BioLegend, mean 7.13pg/ml IL-34 [ 23 ], median 83pg/ml IL-8 [ 24 ], mean 1.91pg/ml IFNγ [ 25 ], mean 0.74pg/ml IL1α [ 26 ], mean 1.85pg/ml IL1β [ 27 ], mean 312pg/ml PGE2, ThermoFisher).…”

Section: Methodsmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation

et al. 2022

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The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB). Interactions between PDAC CTC and M-FB in the portal blood promotes the formation of immunoresistant clusters that enhance CTC proliferation, migration, and survival. Analysis of portal and peripheral blood samples collected intraoperatively from 30 PDAC patients undergoing pancreatico-duodenectomy showed that PDAC patient plasma contained high levels of macrophage colony stimulating factor (M-CSF/CSF1), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2), interleukin-8 (IL-8), and interleukin-34 (IL-34) compared to healthy control levels. Moreover, the level of M-CSF in portal blood was significantly higher than that detected in the peripheral blood of PDAC patients. PDAC CTC aseptically isolated by fluorescence activated cell sorting (FACS) out of freshly collected patient portal blood mononuclear cells (PortalBMC) had elevated RNA expression of IL34 (IL-34 gene) and CSF1 (M-CSF/CSF1 gene) which both signal through CSF1R. PDAC CTC also had high levels of RNA expression for CXCL8, the gene encoding chemokine interleukin-8 (IL-8) which can attract myeloid cells through their CXCR2 receptors. FACS-isolated portal PDAC CTC and M-FB co-cultured ex vivo had increased CTC proliferation, motility, and cluster formation compared to CTC cultured alone. CSF1R and CXCR2 cell surface expression were found on PDAC portal blood CTC and M-FB, suggesting that both cell types may respond to M-CSF, IL-34, and IL-8-mediated signaling. Portal PDAC CTC displayed enhanced RNA expression of CSF1 and IL34, while CTC+M-FB+ clusters formed in vivo had increased RNA expression of CSF2 and IL34. Portal M-FB were found to have high CSF1R RNA expression. CTC isolated from ex vivo 7-day cultures of PDAC patient portal blood mononuclear cells (PortalBMC) expressed elevated CSF1, IL34, and IL8 RNA, and CSF1 expression was elevated in M-FB. Treatment with rabbit anti-CSF1R antibodies decreased CTC proliferation. Treatment of PortalBMC cultures with humanized anti-CSF1R, humanized anti-IL-8, or anti-IL-34 antibodies disrupted CTC cluster formation and increased CTC apoptosis. U937 myeloid precursor cell line cultures treated with conditioned media from PortalBMC ex vivo cultures without treatment or treated with anti-IL-8 and/or anti-CSF1R did not prevent myeloid differentiation in the myeloid precursor cell line U937 to macrophage, dendritic cell, MDSC, and M-FB phenotypes; whereas, U937 cultures treated with conditioned media from PortalBMC ex vivo cultures exposed to anti-IL-34 were significantly inhibited in their myeloid differentiation to all but the M-FB phenotype. PDAC patient T cells that were found phenotypically anergic (CD3+CD25+CTLA4+PD1L1+) in PortalBMC could be re-activated (CD3+CD25+CTLA4-PD1L1-), and displayed increased interferon gamma (IFNγ) production when PortalBMC ex vivo cultures were treated with anti-CSF1R, anti-IL-8, and anti-IL-34 antibodies alone or in combination. These findings suggest that PDAC CTC have the potential to influence myeloid differentiation and/or antigen presenting cell activation in the PDAC portal blood microenvironment, and that disruption of CTC/M-FB interactions may be potential targets for reversing the immunosuppression supporting CTC survival in the portal blood.

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Section: Methodsmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation

et al. 2022

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“…Having proven that NEAT1-2 could facilitate the anti-hantaviral activation of macrophages in vitro , we wondered whether these observations were clinically relevant. According to the clinical manifestations and related laboratory parameters of patients, the severity of HFRS can be categorized as mild, moderate, severe or critical, and the disease course can be divided into five classical stages, namely, the febrile, hypotensive shock, oliguric, diuretic, and convalescent stages, of which the former three are collectively referred to as the acute phase, while the latter two are referred to as the convalescent phase ( Ma et al, 2015 ; Tang et al, 2019 ; Liu R. et al, 2021 ). Monocytes were acquired through negative bead screening from the peripheral blood mononuclear cells (PBMCs) of HFRS patients at different clinical stages ( Figure 6A ), and the NEAT1-2 expression level was calculated with the housekeeping gene Gapdh used for normalization.…”

Section: Resultsmentioning

confidence: 99%

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

Yang

Yong

et al. 2022

Front. Microbiol.

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As the global prototypical zoonotic hantavirus, Hantaan virus (HTNV) is prevalent in Asia and is the leading causative agent of severe hemorrhagic fever with renal syndrome (HFRS), which has profound morbidity and mortality. Macrophages are crucial components of the host innate immune system and serve as the first line of defense against HTNV infection. Previous studies indicated that the viral replication efficiency in macrophages determines hantavirus pathogenicity, but it remains unknown which factor manipulates the macrophage activation pattern and the virus-host interaction process. Here, we performed the transcriptomic analysis of HTNV-infected mouse bone marrow-derived macrophages and identified the long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1), especially the isoform NEAT1-2, as one of the lncRNAs that is differentially expressed at the early phase. Based on coculture experiments, we revealed that silencing NEAT1-2 hinders inflammatory macrophage activation and facilitates HTNV propagation, while enhancing NEAT1-2 transcription effectively restrains viral replication. Furthermore, sterol response element binding factor-2 (SREBP2), which controls the cholesterol metabolism process, was found to stimulate macrophages by promoting the production of multiple inflammatory cytokines upon HTNV infection. NEAT1-2 could potentiate SREBP2 activity by upregulating Srebf1 expression and interacting with SREBP2, thus stimulating inflammatory macrophages and limiting HTNV propagation. More importantly, we demonstrated that the NEAT1-2 expression level in patient monocytes was negatively correlated with viral load and HFRS disease progression. Our results identified a function and mechanism of action for the lncRNA NEAT1 in heightening SREBP2-mediated macrophage activation to restrain hantaviral propagation and revealed the association of NEAT1 with HFRS severity.

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“…In recent years, several studies have explored some early warning indicators which can re ect the severity and predict the prognosis of HFRS, such as interleukin-34, adiponectin, pentraxin-3, interleukin-6, tumour necrosis factor-α (TNF-α), sCD163, growth arrest-speci c 6 protein, urinary neutrophil gelatinase-associated lipocalin (NGAL), etc. [19][20][21][22][23][24][25]. For the reasons that the high cost of detection, complicated operation methods and limited predictive effectiveness, however, the above indicators are not extensively used in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

The Expression of Serum Ferritin and Its Clinical Predictive Value in Patients With Hemorrhagic Fever With Renal Syndrome

Wang

Lian

et al. 2021

Preprint

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As a natural focus disease characterized by systemic immunopathological injury, there is a considerable diversity and heterogeneity in clinical course and prognosis of the patients with hemorrhagic fever with renal syndrome (HFRS). Therefore, the importance of early prediction and prognostic evaluation of severe patients in reducing mortality is self-evident. In this study, we detected the expression of serum ferritin and investigated its role on disease severity assessment and prognosis prediction in HFRS patients. The levels of serum ferritin in acute phase were higher than that of healthy controls and in convalescent phase of the same type, and gradually increased with the aggravation of the disease, which showed highest expression in the critical-type patients. Serum ferritin demonstrated significant correlations with conventional laboratory parameters (WBC, PLT, AST, ALB, APTT, Fib) and the length of hospital stay. High levels of ferritin were significantly associated with the death of HFRS, with a hazard ratio of 4.12. Serum ferritin showed a comparable predictive efficacy for the prognosis (death) of HFRS with that of conventional laboratory parameters, which with the AUC of 0.860 (95%CI: 0.782 ~ 0.938, P < 0.001). These results indicated that the detection of serum ferritin might be beneficial to early prediction and prognosis evaluation in severe HFRS patients and which is worthy of clinical application.

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Elevated plasma interleukin 34 levels correlate with disease severity-reflecting parameters of patients with haemorrhagic fever with renal syndrome

Cited by 12 publications

References 43 publications

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

The Expression of Serum Ferritin and Its Clinical Predictive Value in Patients With Hemorrhagic Fever With Renal Syndrome

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