Increased Serum Levels of the IL‐33 Neutralizing sST2 in Limited Cutaneous Systemic Sclerosis

Abstract

The pathophysiology of both limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous SSc (dcSSc), representing two subtypes of an autoimmune disease of the connective tissue, is still enigmatic. Life-limiting, progressive fibrotic changes as a consequence of vasculopathy and autoimmunity are characteristic in varying extent for lcSSc and dcSSc. Previously, an increased IL-33 serum concentration in early phase SSc patients and an elevated tissue expression of its receptor, ST2L, on endothelial cells (EC) were described. While suggested as a biomarker for fibrotic diseases, for example liver fibrosis, the role of soluble ST2 (sST2) in the pathological processes and its contribution to vascular fibrosis in SSc has not been investigated. Here, we showed that sST2 is elevated in late phase limited cutaneous SSc (lcSSc) as compared to patients with shorter disease duration or with the diffuse subtype of SSc. We demonstrated that sST2, not IL-33, is significantly increased in serum of lcSSc patients with disease duration over 9 years. Soluble ST2 was not elevated in healthy controls or in SSc patients with early skin involvement or disease duration shorter than 9 years. Furthermore, we observed that sST2 serum levels were lowered by iloprost (prostacyclin) treatment. After 5 days of iloprost infusion, sST2 serum levels fell in 6 of 7 patients. Therefore, we not only like to propose sST2 as a biomarker for progressive vascular fibrosis, but moreover, suggest that the involvement of sST2 in the pathogenesis of lcSSc may be exploited therapeutically.

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

“…Finally, the expanding roles of the ST2/IL-33 axis in type 2 diabetes and obesity (68), pulmonary arterial hypertension (69), and idiopathic pulmonary fibrosis as well as systemic sclerosis (70,71) suggest that therapeutic development of ST2 inhibitors will have a broad impact on disease management beyond GVHD.…”

IL-33/ST2 Axis in Organ Fibrosis

“…Conversely, sST2 constitutes a potential marker for disease progression in limited cutaneous SSc with disease duration over 9 years. On the contrary, sST2 was not elevated in healthy controls or SSc patients with early skin involvement or disease duration shorter than 9 years ( 157 ). Furthermore, sST2 serum levels were lowered by iloprost (prostacyclin) treatment ( 157 ).…”

“…On the contrary, sST2 was not elevated in healthy controls or SSc patients with early skin involvement or disease duration shorter than 9 years ( 157 ). Furthermore, sST2 serum levels were lowered by iloprost (prostacyclin) treatment ( 157 ). The question remains why sST2 is elevated in limited cutaneous SSc and not in diffuse cutaneous SSc patients.…”

Contribution of Interleukin-6 to the Pathogenesis of Systemic Sclerosis

“…fibrosisandendothelialdamage (9)(10)(11)(12)(13)(14)(15)(16)(17)(18).Thefindingsofthese experimental studies provided the rationale for developing noveltargetedtherapiesinSSc,whichhavebeenevaluatedin severalclinicaltrialsinthepastdecade;however,adiseasemodifyingtherapyhasyettobeapprovedforthisindication. In a recent randomized, double-blind, placebo-controlled, phase2trial,tocilizumab,ananti-IL-6receptor-alpha(IL-6Rα) antibody,wasinvestigatedasatreatmentforskinfibrosisin patients with SSc and was shown to reduce skin thickening andimprovelungfunction (29).…”

“…Systemic sclerosis (SSc) is a complex disease resulting from impaired biological cell function, affecting endothelial cells,fibroblasts,lymphocytes,monocytes,andbonemarrow cells (1)(2)(3)(4).Vasculopathyandtissuefibrosisoccurasaresult oftheseimpairmentsandareconsideredtobethemainclinicalfeaturesofpatientswithSSc.Thesepatientshavedysregulation of genetic and epigenetic function (5-7), innate immunity(8),andresponsetoinfections,resultinginaberrant immuneactivationandacceleratedtissuedamageleadingto tissuefibrosis,vasculopathy,andautoimmunity.Inthepast2 decades,manycytokines (9)(10)(11)(12)(13)(14)(15)(16)(17)(18),chemokines (19)(20)(21),growth factors (22)(23)(24)(25)(26),andtranscriptionfactors (27,28)havebeen studied for their potential involvement in the pathogenesis of SSc. For example, in vitro and in vivo experiments using sclerodermamurinemodelshaverevealedthattransforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and connective tissue growth factor may play crucial roles in collagen production by tissue fibroblasts in SSc (22)(23)(24)(25)(26).Inadditiontothesegrowthfactors,cytokines-including interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-8, IL-13, IL-33, and IL-35 -were found to be potent regulators of tissue…”