Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis

Xu, Shihui; Yang, Xiaobing; Chen, Qingzhou; Liu, Zhuoliang; Chen, Ying; Yao, Xiaotian; Xu, An; Tian, Jing; Xie, Liling; Zhou, Miaomiao; Hu, Zheng; Zhu, Feiqi; Xu, Xin; Hou, Fanfan; Nie, Jing

doi:10.1016/j.ebiom.2022.104312

Cited by 21 publications

(11 citation statements)

References 96 publications

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“…Our ligand-receptor analysis identi ed multiple signaling pathways by which the in ammatory tubular cells mediate leucocyte chemotaxis and broblast-to-myo broblast activation and our spatial analysis con rmed that the ligands and receptors are in close proximity to enable effective signaling. Inhibition of several of these ligandreceptor pairs is e cacious in murine kidney disease (13,29,32,43,44) and our data suggest that they offer new therapeutic opportunities in human disease.…”

Section: Discussionmentioning

confidence: 73%

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

Conway,

Reck,

Baird

et al. 2024

Preprint

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Maladaptive proximal tubular cells have been implicated in failure of repair following renal injury in rodent models, however whether this translates to human kidney disease is unknown. Hence, we integrated snRNA-ATAC-seq with single-cell molecular imaging to generate a multiomic atlas of human kidney disease. In injured kidneys, a subset of tubular epithelial cells acquired an inflammatory phenotype, enriched with pro-fibrotic and senescence markers, analogous to maladaptive cells in mice. Cell neighborhood analysis positioned the inflammatory phenotype adjacent to leucocytes and myofibroblasts and ligand-receptor analysis highlighted paracrine signaling from inflammatory tubular cells to mediate leucocyte recruitment and myofibroblast activation. Loss of an HNF4α-driven gene regulatory network and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting these inflammatory tubular cells by administration of an AP-1 inhibitor or a senolytic agent ameliorated inflammation, expression of senescence-associated transcripts and fibrosis in murine models of kidney injury suggesting these as therapies for human kidney disease.

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Section: Discussionmentioning

confidence: 73%

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

Conway,

Reck,

Baird

et al. 2024

Preprint

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“…The LIF-neutralizing antibody attenuated TIF induced by UUO and UIRI. Our study provides evidence that LIF might be a potential therapeutic target of TIF [83]. In addition, our study suggests systemic analysis of the expression of whole family members is needed to identify the most critical member in certain disease state.…”

Section: Lif In Organ Fibrosismentioning

confidence: 82%

Role of Interleukin-6 Family Cytokines in Organ Fibrosis

Chen¹,

Zhou²,

Xu³

et al. 2023

Kidney Dis

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Background: Organ fibrosis remains an important cause of high incidence rate and mortality worldwide. The prominent role of interleukin-6 (IL-6) family members represented by IL-6 in inflammation has been extensively studied, and drugs targeting IL-6 have been used clinically. Because of the close relationship between inflammation and fibrosis, researches on the role of IL-6 family members in organ fibrosis are also gradually emerging. Summary: In this review, we systematically reviewed the role of IL-6 family members in fibrosis and their possible mechanisms. We listed the role of IL-6 family members in organ fibrosis, and drew two diagrams to illustrate the downstream signal transductions of IL-6 family members. We also summarized the effect of some IL-6 family members' antagonists in a table. Key Messages: Fibrosis contributes to organ structure damage, organ dysfunction and eventually organ failure. Although IL-6 family cytokines have similar downstream signal pathways, different members play various roles in an organ-specific manner which might partly due to their different target cell populations. The pathogenic role of individual member in various diseases needs to be deciphered carefully.

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“…Leukemia inhibitory factor receptor (LIF-R), a receptor for the multifunctional cytokines like LIF, is intimately connected with renal interstitial fibrosis and CKD progression. LIF, part of the IL-6 cytokine family, is notably upregulated in fibrotic renal lesions, inversely correlating with eGFR, and presenting as a potential biomarker for CKD [ 60 ]. LIF-R's modulation has shown promise in experimental models, where its knockdown mitigates RIF, while its upregulation aggravates it, marking the LIF/LIF-R axis as a potential therapeutic target for kidney fibrosis and CKD progression.…”

Section: Discussionmentioning

confidence: 99%

Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization

Hu,

Hao,

et al. 2024

Clin Exp Med

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Prior research has established associations between immune cells, inflammatory proteins, and chronic kidney disease (CKD). Our Mendelian randomization study aims to elucidate the genetic causal relationships among these factors and CKD. We applied Mendelian randomization using genetic variants associated with CKD from a large genome-wide association study (GWAS) and inflammatory markers from a comprehensive GWAS summary. The causal links between exposures (immune cell subtypes and inflammatory proteins) and CKD were primarily analyzed using the inverse variance-weighted, supplemented by sensitivity analyses, including MR-Egger, weighted median, weighted mode, and MR-PRESSO. Our analysis identified both absolute and relative counts of CD28 + CD45RA + CD8 + T cell (OR = 1.01; 95% CI = 1.01–1.02; p < 0.001, FDR = 0.018) (OR = 1.01; 95% CI = 1.00–1.01; p < 0.001, FDR = 0.002), CD28 on CD39 + CD8 + T cell(OR = 0.97; 95% CI = 0.96–0.99; p < 0.001, FDR = 0.006), CD16 on CD14–CD16 + monocyte (OR = 1.02; 95% CI = 1.01–1.03; p < 0.001, FDR = 0.004) and cytokines, such as IL-17A(OR = 1.11, 95% CI = 1.06–1.16, p < 0.001, FDR = 0.001), and LIF-R(OR = 1.06, 95% CI = 1.02–1.10, p = 0.005, FDR = 0.043) that are genetically predisposed to influence the risk of CKD. Moreover, the study discovered that CKD itself may causatively lead to alterations in certain proteins, including CST5(OR = 1.16, 95% CI = 1.09–1.24, p < 0.001, FDR = 0.001). No evidence of reverse causality was found for any single biomarker and CKD. This comprehensive MR investigation supports a genetic causal nexus between certain immune cell subtypes, inflammatory proteins, and CKD. These findings enhance the understanding of CKD's immunological underpinnings and open avenues for targeted treatments.

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Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis

Cited by 21 publications

References 96 publications

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

Role of Interleukin-6 Family Cytokines in Organ Fibrosis

Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization

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