Potential Role of Humoral IL-6 Cytokine in Mediating Pro-Inflammatory Endothelial Cell Response in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease with limited therapeutic options. Numerous intrinsic and extrinsic factors are involved in ALS motor neuron degeneration. One possible effector accelerating motor neuron death in ALS is damage to the blood-Central Nervous System barrier (B-CNS-B), mainly due to endothelial cell (EC) degeneration. Although mechanisms of EC damage in ALS are still unknown, vascular impairment may be initiated by various humoral inflammatory factors and other mediators. Systemic IL-6-mediated inflammation is a possible early extrinsic effector leading to the EC death causing central nervous system (CNS) barrier damage. In this review, we discuss the potential role of humoral factors in triggering EC alterations in ALS. A specific focus was on humoral IL-6 cytokine mediating EC inflammation via the trans-signaling pathway. Our preliminary in vitro studies demonstrated a proof of principle that short term exposure of human bone marrow endothelial cells to plasma from ALS patient leads to cell morphological changes, significantly upregulated IL-6R immunoexpression, and pro-inflammatory cell response. Our in-depth understanding of specific molecular mechanisms of this humoral cytokine in EC degeneration may facilitate an endothelial-IL-6-targeting therapy for restoring cell homeostasis and eventually reestablishing B-CNS-B integrity in ALS.

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

“…One study suggested that this was a response to hypoxia rather than to the disease itself (137) (see below). IL-6 has been suggested to have a role in endothelial damage in ALS (138). Genetic variation in the IL-6 receptor has been shown to modify the severity of ALS (88).…”

Glia Crosstalk in Neuroinflammatory Diseases

“…Additionally, TREM 2 is also overexpressed and correlates negatively with patient’s prognosis, being a potential biomarker for the disease (Cady et al, 2014 ). Activated microglia can induce oxidative stress via ROS and NO and proinflammatory cytokines such as TNF-α, IL-6, and IL-1β, which induce MN cell death (Garbuzova-Davis et al, 2018 ). These cytokines activate astrocytes, which also affect ALS onset and development by two different approaches.…”

Incremento de la viabilidad, producción de especies reactivas de oxígeno, IL-1 y TNF-α en células mononucleares de sangre periférica humana tratadas con fucoidan de Lessonia trabeculata

“…La IL-6 es una citoquina bifuncional que media actividades pro y antiinflamatorias. Esta citoquina es expresada por neutrófilos y eosinófilos no estimulados, linfocitos B y T, monocitos y células endoteliales estimuladas (Garbuzova-Davis et al 2018). En los cultivos tratados con FLt y FFv se evidenció la producción de IL-6 (p>0.05).…”