The RNFT2/IL-3Rα axis regulates IL-3 signaling and innate immunity

Tong, Yao; Evankovich, John; Chen, Yanwen; Londino, J.D.; Myerburg, Michael M.; Zhang, Yingze; Popescu, Iulia; McDyer, John F.; McVerry, Bryan J.; Lockwood, Karina C.; Jurczak, Michael J.; Liu, Yuan; Chen, Bill B.

doi:10.1172/jci.insight.133652

Cited by 20 publications

(15 citation statements)

References 57 publications

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“…Our results also suggested that both CD123 and its cognate ligand, the IL-3 cytokine, play an important role in sepsis. High IL-3 plasma levels have been associated with lung inflammation, lung injury, and high mortality rates in an animal model, as well as in humans ( 25 , 26 ). IL-3 neutralization and anti-CD123 treatment improved mice outcome by decreasing inflammation and mortality rates ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications

et al. 2021

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BackgroundLymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.ObjectiveWe investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients’ clinical characteristics.MethodsWe used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.ResultsThe Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10−CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1β, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions.ConclusionLOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

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Section: Discussionmentioning

confidence: 99%

LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications

et al. 2021

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“…It is highly expressed in the brain and testis and ubiquitously expressed in multiple organs including the gastrointestinal tract, liver, adrenal gland, and lung. RNFT2 has been reported to decrease lung inflammation and damage by ubiquitinating and degrading IL-3Ra, the receptor for the IL-3 inflammatory cytokine (10). There have been no reports of an association between malignancy and RNFT2 and only a few reports suggest that RNFT1 is involved in the suppression of metastasis in breast cancer (11).…”

Section: Discussionmentioning

confidence: 99%

TissueRNFT2Expression Levels Are Associated With Peritoneal Recurrence and Poor Prognosis in Gastric Cancer

et al. 2021

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Background/Aim: Disease recurrence is frequently observed after curative resection of advanced gastric cancer resulting in a poor prognosis. In the present study, we identified a candidate biomarker to predict recurrence and prognosis after curative resection of gastric cancer. Materials and Methods: A transcriptome analysis was conducted using surgically resected cancerous tissue from patients with metastatic gastric cancer to identify genes that are upregulated in primary and metastatic tissues. Results: Ring finger protein, transmembrane 2 (RNFT2) mRNA expression was upregulated in primary gastric cancer tissues and metastases compared with non-cancerous tissues. RNFT2 expression in gastric cancer cell lines was positively correlated with the EMT-related molecules GSC, MMP9, and RAC1. The RNFT2 high expression group exhibited a significantly shorter postoperative overall survival. Peritoneal recurrence was significantly higher in the RNFT2 high expression group. Conclusion: RNFT2 mRNA expression predicts peritoneal recurrence and is a potential prognostic biomarker for gastric cancer following curative gastrectomy.Gastric cancer has become the leading cause of cancerrelated deaths worldwide (1). Despite advances in our understanding of the pathogenesis and treatment of gastric cancer, the recurrence rate after radical gastrectomy remains high and prognosis is poor (2, 3). The identification of biomarkers that predict gastric cancer metastasis and recurrence will enable physicians to predict the risk of recurrence in individual patients (4, 5). Perioperative chemotherapy and postoperative follow-up, considering the respective risks, may contribute to the prevention of recurrence, early detection, and improved prognosis.The type of recurrence and metastasis of gastric cancer include lymph node recurrence, hematogenous metastasis and peritoneal dissemination. Among them, in particular peritoneal metastasis is difficult to detect early and systemic chemotherapy is largely ineffective. As a result, peritoneal metastasis is a major cause of poor prognosis in gastric cancer (6).Defining the risk of peritoneal metastasis is necessary for prediction and early detection, but there are currently no established biomarkers.To identify differentially expressed genes that associate with the metastasis of gastric cancer, we conducted a transcriptome analysis of gastric clinical specimens from patients with distant metastasis. We identified a ring finger protein, transmembrane 2 (RNFT2), as a novel candidate biomarker. RNFT2 has been implicated in mediating protein interactions and the ubiquitination of target proteins, but its role in gastric cancer has not been reported. In the present study, we investigated the relationship between RNFT2 mRNA expression in gastric cancer tissues and the likelihood of recurrence after curative gastrectomy. Materials and MethodsEthics. This study conformed to the ethical guidelines of the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human...

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“…It was notably that since CD123 was also restrictedly expressed on normal cells, resulting in side effects such as cytokines storm (Tong et al, 2020 ). Currently, cytokine storm syndrome (CSS) caused by CD123-targeted therapy is a major fatal factor during clinical treatment and hindered therapeutic effects severely (Chousterman et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Novel CD123 polyaptamer hydrogel edited by Cas9/sgRNA for AML-targeted therapy

Zhang

Zhu

et al. 2021

Drug Delivery

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CD123 targeting molecules have been widely applied in acute myelocytic leukemia (AML) therapeutics. Although antibodies have been more widely used as targeting molecules, aptamer have unique advantages for CD123 targeting therapy. In this study, we constructed an aptamer hydrogel termed as SSFH which could be precisely cut by Cas9/sgRNA for programmed SS30 release. To construct hydrogel, rolling-circle amplification (RCA) was used to generate hydrogel containing CD123 aptamer SS30 and sgRNA-targeting sequence. After incubation with Cas9/sgRNA, SSFH could lose its gel property and liberated the SS30 aptamer sequence, and released SS30 has been confirmed by gel electrophoresis. In addition, SS30 released from SSFH could inhibit cell proliferation and induce cell apoptosis in vitro . Moreover, SSFH could prolong survival rate and inhibit tumor growth via JAK2/STAT5 signaling pathway in vivo . Additionally, molecular imaging revealed SSFH co-injected with Cas9/sgRNA remained at the injection site longer than free aptamer. Furthermore, once the levels of cytokines were increasing, the complementary sequences of aptamers injection could neutralize SS30 and relieve side effect immediately. This study suggested that CD123 aptamer hydrogel SSFH and Cas9/sgRNA system has strong potential for CD123-positive AML anticancer therapy.

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The RNFT2/IL-3Rα axis regulates IL-3 signaling and innate immunity

Cited by 20 publications

References 57 publications

LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications

LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications

TissueRNFT2Expression Levels Are Associated With Peritoneal Recurrence and Poor Prognosis in Gastric Cancer

Novel CD123 polyaptamer hydrogel edited by Cas9/sgRNA for AML-targeted therapy

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