Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence

Abstract

Chronic venous disease is a condition globally widespread, resulting in a disabling pathological disorder. The CD4 + Th17+ (Cluster Differentiation 4) lymphocytes represent a regulative factor for innate immunity related to the development of complex diseases. Recently, these mechanisms have been associated with vascular disease. The aim of this work is to validate whether the Th17 response correlates with the development of CVI (Chronic venous insufficiency)and CVLUs (chronic venous limbs ulcers) and whether Th17 markers can be used, both as intrinsic risk factors and diagnostic markers, for disease development. PBL derived from peripheral blood samples of patients and controls were subjected to gene expression analysis for IL23R, IL17, SGK1, TGFβ, RORγ, FOXO1, and RANBP1 by qRT-PCR and immunoblot. A post hoc correlation, the diagnostic performance of the target genes, and multivariable analyses were properly conducted. The main expression markers of the CD4 + Th17+ switch were strongly activated in chronic venous insufficiency and in advanced ulceration. The correlation analysis demonstrated the inter-dependence on Th17’s signature modulation. ROC (Receiver Operating Characteristic) analysis defined, for the examined genes, a clinical value as the potential diagnostic markers. Multi-logistic regression studies showed that Th17 markers behave as empirical risk factors for CVD (chronic venous disease) development. Taken together, the present data provide a new hypothesis for the TH17-dependent pathogenesis of CVD, favoring the possibility for the development of new diagnostic, preventive, and therapeutic approaches.

RANBP1, a member of the nuclear-cytoplasmic trafficking-regulator complex, is the terminal-striking point of the SGK1-dependent Th17+ pathological differentiation

“…Having shown that RANBP1 is endogenously correlated to both early and late Th17 + differentiation phase and that RANBP1 fluctuations are able of conditioning the fate of this differentiative process by ultimately modulating SGK1-dependent signaling, we wondered through which mechanism RANBP1 may affect the IL-23R-SGK1-FOXO1-RORγt signal transduction ( 17 , 21 , 22 , 24 ). RANBP1, during interphase, controls nuclear import/export by activating the RANGAP1-dependent GTP-hydrolytic activity on RAN ( 26 , 30 , 31 ).…”

“…These cytokines induce the transcription factor RORgt, which, cooperating with RORa and other transcription factors, promotes the expression of IL-17A and IL-23R on maturating Th17 + cells (20). Our previous data, obtained in vivo models, demonstrated that SGK1 contributed to Th17 + transition in an experimental system of ulcerative colitis and chronic venous disease, with obvious pathological effects on disease targets (21,22). SGK1 appears to play a critical role in the modulation of Treg/Th17 phenotype, through phosphorylation-dependent control of the nuclear-cytoplasmic FOXO1 localization (23,24).…”

Chronic Venous Disease: Pathophysiological Aspects, Risk Factors, and Diagnosis

“…Finally, multivariable analysis identified IL23R, IL17, RORγ, and RANBP1 as potential risk factors for developing CVD and chronic venous leg ulcerations. 88 The significance of venous hypertension in the inflammatory process is underscored by the fact that even just 30 minutes of quiet standing can trigger an inflammatory response. 89…”

Molecular Determinants of Chronic Venous Disease: A Comprehensive Review

“…A recent study postulated that T-helper-17 (Th17) gene expression may influence CVD onset and progression. Th17 cells are a subtype of pro-inflammatory T helper (CD4+) cells, defined by the production of a cytokine signature, of which IL17 represents the progenitor and may be a role in chronic inflammation that characterizes CVD in its progression to the most severe stages [42].…”