Eltrombopag in paediatric immune thrombocytopenia: Iron metabolism modulation in mesenchymal stromal cells

Abstract

Summary Immune thrombocytopenia (ITP) is an autoimmune disease caused by platelet destruction mediated by auto‐antibody production. It is characterized by a compromised immune system and alteration of the inflammatory response. Mesenchymal stromal cells (MSCs) play an important role in modulating immune and inflammatory processes, exerting immune‐suppressing and anti‐inflammatory properties. In ITP‐MSCs the activity and survival are strongly impaired. Eltrombopag (ELT) is a thrombopoietin receptor agonist approved in chronic ITP for stimulating platelet production. It has immunomodulating properties by stimulating T and B regulatory cell activity and by promoting a macrophage switch from the pro‐inflammatory to the anti‐inflammatory phenotype. ELT also exhibits iron‐chelating properties. Iron is a crucial element involved in several physiologic processes, but its intracellular accumulation determines cell damages. Therefore, for the first time we analysed the effect of ELT on ITP‐MSCs demonstrating its ability to restore survival and activity of MSCs directly and to promote their survival and proliferation indirectly, by iron metabolism modulation.

Effects of eltrombopag on mesenchymal stem cells in immune thrombocytopenia purpura

“…Moreover, in line with past work by Spitz et al 7 who demonstrated that ELT is a direct inhibitor of pro-apoptotic BAX, Di Paola et al 1 also found moderately reduced apoptosis rates in MSC and a strong upregulation of anti-apoptotic BCL-2 following ELT treatment. Whether the reduced ferric iron content in ITP-MSC contributes to differential regulation of BCL-2, changes in cell survival, or any other cell functions upon ELT treatment remains to be determined.…”

“…This study 1 provides proof‐of‐concept data supporting aberrant iron loading of MSC in ITP; it sheds further light on the mechanistic underpinnings of ELT in this disease, which may also be a starting point to better understand the absence of cross‐resistance to TPO‐RA in ITP 12 ; and it suggests that ELT may be beneficial for normalising the immune modulatory activities and survival of MSC in patients, which may provide another path to curtailing abnormal immune function in ITP. Further work will need to address the prevalence of iron loading in MSC of patients with ITP and validate the authors’ findings in vivo.…”

“…This suggests that ELT normalises PLT numbers, at least partially, through TPO-R-independent mechanisms. [6][7][8] Di Paola et al 1 assessed the consequences of ELT in ITP patient-derived mesenchymal stem cells (MSC), which are not known to express TPO-R. The authors found that ex vivo exposure of the small molecule reduced aberrantly elevated ferric iron content in ITP patient-derived MSC (ITP-MSC) consistent with its ferric iron chelating property.…”

“…The authors found that ex vivo exposure of the small molecule reduced aberrantly elevated ferric iron content in ITP patient-derived MSC (ITP-MSC) consistent with its ferric iron chelating property. 9 Di Paola et al 1 found further that ELT attenuated abnormally increased pro-inflammatory interferon-γ (IFN-γ), as well as interleukin-6 (IL-6); although how lower ferric iron loading upon ELT may directly affect the release of pro-inflammatory cytokines from MSC remains to be investigated. Infections and autoimmune disease trigger an increased production of various cytokines, including IL-6 which is a key activator of hepcidin-controlled iron homeostasis 10 limiting intestinal iron absorption and release of recycled iron by macrophages through impairing ferroportin-1 (FPN-1).…”

Emerging Roles of the Iron Chelators in Inflammation

“…Eltrombopag (ELT) is an orally available thrombopoietin receptor agonist responsible for the stimulation of platelet production, currently approved for the treatment of chronic immune thrombocytopenia when both first-line therapy and splenectomy fail [ 101 , 103 , 104 ]. It is also used in refractory aplastic anemia, and in patients with thrombocytopenia secondary to hepatitis C during treatment with interferon [ 104 ].…”