CXCL14 Overexpression Attenuates Sepsis-Associated Acute Kidney Injury by Inhibiting Proinflammatory Cytokine Production

Lv, Jing; Wu, Zhilin; Gan, Zheng; Gui, Ping; Yao, Shanglong

doi:10.1155/2020/2431705

Cited by 13 publications

(17 citation statements)

References 31 publications

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“…This activation may lead to favorable or unfavorable gene expression changes for host cells and contribute to ARDS shown in some COVID-19 patients [ 56 ]. In addition to the pathways, inflammatory chemokines, such as C–X–C motif chemokine ligand 1 ( CXCL1 ), CXCL2 , CXCL3 , CXCL5 and CXCL6 , were significantly upregulated as previously reported [ 24 ], while CXCL14 with anti-inflammatory activity [ 57 ] was substantially downregulated ( Table S1 ). Several interleukin genes, including interleukin 1 alpha ( IL1A ), IL1B , IL32 , IL36G , IL6 and IL8 , were also upregulated in SARS-CoV-2-infected NHBE cells along with SOCS3, which has been shown to function as an IL-6 inhibitor [ 58 , 59 ].…”

Section: Discussionsupporting

confidence: 75%

Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

Kang

Kim

Choi

2020

Viruses

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The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects almost everyone in the world in many ways. We previously predicted antivirals (atazanavir, remdesivir and lopinavir/ritonavir) and non-antiviral drugs (tiotropium and rapamycin) that may inhibit the replication complex of SARS-CoV-2 using our molecular transformer–drug target interaction (MT–DTI) deep-learning-based drug–target affinity prediction model. In this study, we dissected molecular pathways upregulated in SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells by analyzing an RNA-seq data set with various bioinformatics approaches, such as gene ontology, protein–protein interaction-based network and gene set enrichment analyses. The results indicated that the SARS-CoV-2 infection strongly activates TNF and NFκB-signaling pathways through significant upregulation of the TNF, IL1B, IL6, IL8, NFKB1, NFKB2 and RELB genes. In addition to these pathways, lung fibrosis, keratinization/cornification, rheumatoid arthritis, and negative regulation of interferon-gamma production pathways were also significantly upregulated. We observed that these pathologic features of SARS-CoV-2 are similar to those observed in patients with chronic obstructive pulmonary disease (COPD). Intriguingly, tiotropium, as predicted by MT–DTI, is currently used as a therapeutic intervention in COPD patients. Treatment with tiotropium has been shown to improve pulmonary function by alleviating airway inflammation. Accordingly, a literature search summarized that tiotropium reduced expressions of IL1B, IL6, IL8, RELA, NFKB1 and TNF in vitro or in vivo, and many of them have been known to be deregulated in COPD patients. These results suggest that COVID-19 is similar to an acute mode of COPD caused by the SARS-CoV-2 infection, and therefore tiotropium may be effective for COVID-19 patients.

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Section: Discussionsupporting

confidence: 75%

Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

Kang

Kim

Choi

2020

Viruses

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“…These findings are in line with our transcriptome data showing that Retnla, a hallmark of alternatively activated M2 macrophages, was significantly downregulated in cKO mice [ 44 ]. Moreover, CXCL14, a chemokine that has been recently described as inhibiting M1 macrophage polarization but increasing M2 polarization, was markedly reduced in SM-CXCL12 −/− mice, supporting a proinflammatory state [ 45 ]. Previous studies have shown that cardiac M2-like macrophages exhibit tremendous anti-inflammatory and tissue repair capabilities, whereas M1-like macrophages rather reflect a pro-inflammatory status after MI [ 44 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy

Ghadge

Messner

Seiringer

et al. 2021

IJMS

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The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12−/−). SM-CXCL12−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

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“…CXCL14/BRAK promotes chemotaxis of immature dendritic cells, neutrophils, monocytes, activated human NK cells, and others [137]. CXCL14 has been detected in kidney specimens, however, it has not been extensively investigated, except for a study where CXCL14 overexpression mitigates sepsis-induced AKI, probably through the regulation of the M1/M2 macrophage ratio and the downregulation of cytokine production [138].…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

Magkrioti

Antonopoulou

Fanidis

et al. 2022

IJMS

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Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells in this process. Lysophosphatidic acid (LPA) is a bioactive lipid that signals mainly through its six cognate LPA receptors and is implicated in several chronic inflammatory pathological conditions. In this report, we have stimulated human proximal tubular epithelial cells (HKC-8) with LPA and 175 other possibly pathological stimuli, and simultaneously detected the levels of 27 intracellular phosphoproteins and 32 extracellular secreted molecules with multiplex ELISA. This quantification revealed a large amount of information concerning the signaling and the physiology of HKC-8 cells that can be extrapolated to other proximal tubular epithelial cells. LPA responses clustered with pro-inflammatory stimuli such as TNF and IL-1, promoting the phosphorylation of important inflammatory signaling hubs, including CREB1, ERK1, JUN, IκΒα, and MEK1, as well as the secretion of inflammatory factors of clinical relevance, including CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8, most of them shown for the first time in proximal tubular epithelial cells. The identified LPA-induced signal-transduction pathways, which were pharmacologically validated, and the secretion of the inflammatory factors offer novel insights into the possible role of LPA in CKD pathogenesis.

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CXCL14 Overexpression Attenuates Sepsis-Associated Acute Kidney Injury by Inhibiting Proinflammatory Cytokine Production

Cited by 13 publications

References 31 publications

Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy

Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

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