Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

Abstract

Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy. Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients. Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation. Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN. Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs. The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin. In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

COVID-19 Associated Illnesses From Alveoli to Glomeruli: A Case Report

“…Other mechanisms postulated for AKI in COVID-19 include hemodynamic instability, drug toxicity, microthrombi in the renal vasculature, and cytokine-induced damage as part of the cytokine storm [ 11 ]. The SARS-CoV-2 induced cascade of events has been hypothesized to include circulating galactose deficient IgA1 (gd-IgA1) antibodies, formation of autoreactive antibodies to gd-IgA1, early conversion to IgA response, hyperactivation of IgA response in COVID-19 patients and development of immune complexes that deposit in various tissues such as skin, soft tissues, and kidneys [ 12 ].…”

The Human Virome and Its Crosslink with Glomerulonephritis and IgA Nephropathy

“…However, these data may further support the involvement of the PKR in IgAN through its binding to COVID 19 RNA [ 124 ].…”

“…Our recent data show that the VTRNA2-1/PKR/CREB/IL-6 pathway is upregulated in IgAN patients and that it is responsible for the elevated IL-6 levels characterizing the disease [ 124 ].…”

“…It was shown that human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1 and that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract [ 125 ]. Another study showed instead that PKR is regulated by EBV RNA [ 124 ]. These studies support therefore the involvement of viruses in IgAN pathogenesis and in the regulation of the PKR/CREB/IL-6 IgAN pathway.…”

The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview

“…In recent years, pharmacological research has produced a multitude of drugs in an attempt to stop the evolution of chronic kidney disease (CKD). In particular, among rena diseases, many advances in the therapeutic approach for IgAN have been made, mainl thanks to the discoveries in understanding the pathogenesis of this rare glomerulonephri tis that have been achieved (Figure 1) [1,2]. IgAN remains the most common primary glomerulonephritis worldwide [3] and one of the leading causes of ESKD [4].…”