Immunomodulating peptides derived from different human endogenous retroviruses (HERVs) show dissimilar impact on pathogenesis of a multiple sclerosis animal disease model

Abstract

Retroviruses including Human Endogenous Retroviruses (HERVs), contain a conserved region with highly immunomodulatory functions in the transmembrane proteins in envelope gene (env) named immunosuppressive domain (ISU). In this report, we demonstrate that Env59-GP3 peptide holds therapeutic potential in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). The results show that this specific HERV-H derived ISU peptide, but not peptide derived from another env gene HERV-K, decreased the development of EAE in C57BL/6 mice, accompanied by reduced demyelination and inhibition of inflammatory cells. Moreover, here we tested the effect of peptides on macrophages differentiation. The treatment with Env59-GPS peptide modulate the pro-inflammatory M1 profile and anti-inflammatory M2 macrophages, being shown by inhibiting inflammatory M1 hallmark genes/cytokines expression and enhancing expression of M2 associated markers. These results demonstrate that Env59-GP3 ISU peptide has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.

Retroviral Glycoprotein-Mediated Immune Suppression via the potassium Channel KCa3.1- A new strategy for treatment of Inflammatory Bowel Diseases.

“…ENV59-GP3 showed reduction of the disease score in this model, which was comparable to effects of the K Ca 3.1 channel blocker NS6180, though ENV59-GP3 treatment was at five times lower doses (by weight) than that of NS6180. The very low doses of ENV59-GP3 in in vivo treatment regime are in agreement with the treatment results in other animal models [9,10].…”

“…The ENV59-GP3 peptide contains the ISD sequence from a specific human endogenous retroviral protein encoded by the envelope ENV59 gene, originally identified in SLE patients [9], and shown to be adapted by the human immune system to ameliorate autoimmunity [9,10]. In this report, we provide evidence that treatment with the ISD ENV59-GP3 inhibits the development of colitis in dextran sulfate sodium (DSS) -induced mice, a widely recognized autoimmune model of human IBD.…”

“…Recently, we reported identification of an immunosuppressive peptide (ENV59-GP3) from a specific human endogenous retroviral envelope protein, ENV59, which has been adapted by the immune system and is involved in ameliorating autoimmunity [9,10]. The ENV59-GP3 peptide showed strong immune modulating activity both in vitro andin vivo in SKG mouse model for rheumatoid arthritis and EAE model for Multiple Sclerosis [9,10].…”

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

“…A HERV locus coding for envelope protein 59 negatively correlates with interleukin-6 (IL6) and TLR-7 expression. This protein contained an immunosuppressive domain (ISU) which showed strong anti-inflammatory properties in animal models and also in ex vivo experiments in SLE patients, suggesting a potential therapeutic application [154][155][156].…”

The contribution of HERV‐E clone 4‐1 and other HERV‐E members to the pathogenesis of rheumatic autoimmune diseases

“…In fact, env contains an immunosuppressive (ISU) domain, and a pivotal study on SLE and RA patients, THP‐1 leukemia cell line and RA mouse models showed that the Env59 ISU peptide, belonging to HERV‐H3 locus, can exert immune‐modulatory effects on the expression of interleukin (IL)‐6 gene, IFN‐gamma and TLR7 (21). It seems that the tolerogenic properties of the Env59 ISU peptide derive from the polarization of resting macrophages (M0) toward a M2 phenotype, characterized by a strong production of IL‐10 and of other anti‐inflammatory mediators (22). As a consequence, M2 macrophages can impart a downstream tolerogenic signal to immune cells, such as T and B lymphocytes, preventing their activation and inducing, instead, clonal anergy.…”