The Deleterious Impact of Interleukin 9 to Hepatorenal Physiology

Silva, Nadjania Saraiva de Lira; Borges, Bruna Cristina; Silva, Aline Alves da; Castilhos, Patrícia de; Teixeira, Thaíse Lara; Teixeira, Samuel Cota; Santos, Marlus Alves dos; Servato, João Paulo Silva; Justino, Allisson Benatti; Caixeta, Douglas Carvalho; Tomiosso, Tatiana Carla; Espindola, Foued Salmen; Silva, Cláudio Vieira da

doi:10.1007/s10753-019-00997-0

Cited by 9 publications

(7 citation statements)

References 25 publications

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“…Surprisingly, IL-9 was the only cytokine detected much higher in the TKO mice after Ang II treatment compared with Cre mice, which suggested that IL-9 played a crucial role in this perivascular fibrosis phenotype. IL-9 was reported in the regulation of immune responses and involved in the pathogenesis of various inflammatory diseases, 59 including a profibrotic role in lung inflammation and fibrosis, 60 liver fibrosis, 61 and kidney fibrosis. 62 In cardiovascular disease, IL-9 has been implicated in the pathogenesis of atherosclerosis (exerting proatherosclerotic effects) 63 and in heart failure (aggravating isoproterenol-induced heart failure).…”

Section: Discussionmentioning

confidence: 99%

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Zhuang

Chen

Cheng

et al. 2022

Circulation Research

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BACKGROUND: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. METHODS: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient ( Klf10 fl/fl CD4 Cre+ ; [TKO]) and CD4-Cre ( Klf10 +/+ CD4 Cre+ ; (Cre)) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. RESULTS: TF profiling identified increased KLF10 expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice. CONCLUSIONS: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.

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Section: Discussionmentioning

confidence: 99%

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Zhuang

Chen

Cheng

et al. 2022

Circulation Research

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“…However, it is important to note in this context that a recent report contradicts a protective role of IL-9 in renal disease, by demonstrating that long-term IL-9 application (e.g., 40 days) promotes renal collagen deposition. 27 Moreover, several studies have linked chronically increased systemic IL-9 levels to aggravated development of atherosclerosis 23,24 and vein graft disease 25 and showed that anti-IL-9 treatment can confer vascular protection. Especially in light of a strong link between cardiovascular disease and CKD, these considerations are important in assessing the risk for potential side effects of long-term IL-9 therapy, which are likely to be determined by the dose, duration, and context of the cytokine exposure.…”

Section: Discussionmentioning

confidence: 99%

“…While 2 studies suggest that IL-9 is involved in renal tissue protection in models of glomerulonephritis 7 and ischemia-reperfusion injury, 26 a recent investigation contradicted these findings by demonstrating that long-term IL-9 application can promote renal collagen deposition. 27 In this study, we investigated the role of IL-9 in AN, a mouse model of proteinuric CKD and show that IL-9 deficiency leads to increased podocyte damage, aggravated glomerulosclerosis, and impairment of renal function. Moreover, IL-9 overexpression by hydrodynamic gene transfer effectively protected from progressive glomerulosclerosis and kidney failure.…”

mentioning

confidence: 99%

Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy

Xiong

Attar

Gnirck

et al. 2020

Kidney International

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“…To evaluate the effect of IL-9 or its neutralization, the mice were divided into five groups (five animals/group): rIL9 + infected, 9CI + infected, IgG2a (BioXCell) + infected, PBS + infected, and basal (uninfected and untreated) groups. On day -1, all mice received their respective subcutaneous treatment (9CI: 100 µg/ animal, IgG2a: 100 µg/animal (Qin et al, 2016), rIL9: 50 µg/animal (De Lira Silva et al, 2019), or PBS 100µL/animal). On day 0, mice were infected intraperitoneally with 2 × 10 5 TCTs of T. cruzi strain Y and were administered their respective subcutaneous treatment three times per week.…”

Section: In Vivo Experimental Infectionmentioning

confidence: 99%

Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection

Silva

Orikaza

Santana

et al. 2021

Front. Cell. Infect. Microbiol.

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Chagas’ disease is a parasitosis caused by Trypanosoma cruzi, which affects approximately 8 million people worldwide. The balance between pro- and anti-inflammatory cytokines produced during immunological responses contributes to disease prognosis and progression. Parasite tissue persistence can induce chronic inflammatory stimuli, which can cause long-term tissue injury and fibrosis. Chronic Chagas’ patients exhibit increased levels of interleukin (IL)-9, an important cytokine in the regulation of inflammatory and fibrogenic processes. Data on the role of IL-9 in other pathologies are sometimes contradictory, and few studies have explored this cytokine’s influence in Chagas’ disease pathology. Hence, the aim of this study was to evaluate the role of IL-9 in the progression of T. cruzi infection in vivo and in vitro. In vitro infection demonstrated that IL-9 reduced the number of infected cells and decreased the multiplication of intracellular amastigotes in both C2C12 myoblasts and bone marrow-derived macrophages. In myoblasts, the increased production of nitric oxide (NO) was essential for reduced parasite multiplication, whereas macrophage responses resulted in increased IL-6 and reduced TGF-β levels, indicating that parasite growth restriction mechanisms induced by IL-9 were cell-type specific. Experimental infection of BALB/c mice with T. cruzi trypomastigotes of the Y strain implicated a major role of IL-9 during the chronic phase, as increased Th9 and Tc9 cells were detected among splenocytes; higher levels of IL-9 in these cell populations and increased cardiac IL-9 levels were detected compared to those of uninfected mice. Moreover, rIL9 treatment decreased serum IL-12, IL-6, and IL-10 levels and cardiac TNF-α levels, possibly attempting to control the inflammatory response. IL-9 neutralization increased cardiac fibrosis, synthesis of collagens I and III, and mastocyte recruitment in BALB/c heart tissue during the chronic phase. In conclusion, our data showed that IL-9 reduced the invasion and multiplication of T. cruzi in vitro, in both myoblasts and macrophages, favoring disease control through cell-specific mechanisms. In vivo, IL-9 was elevated during experimental chronic infection in BALB/c mice, and this cytokine played a protective role in the immunopathological response during this phase by controlling cardiac fibrosis and proinflammatory cytokine production.

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The Deleterious Impact of Interleukin 9 to Hepatorenal Physiology

Cited by 9 publications

References 25 publications

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy

Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection

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