Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.

Figure. Potential roles of IL-6 signaling and inhibition in NMOSD pathophysiology and treatment

(A) Potential roles for IL-6 signaling in NMOSD pathophysiology. IL-6 induces differentiation of inflammatory Th17 cells from naive T cells, which in turn provide support to AQP4-dependent activated B cells. IL-6 also promotes differentiation of B cells into plasmablasts, inducing production of pathogenic AQP4-IgG. These events are followed by increased BBB permeability to antibodies and proinflammatory cell infiltration into the CNS, leading to binding of AQP4-IgG to AQP4 channels on the astrocytes. In response to stimulation by proinflammatory cytokines, astrocytes produce IL-6, which promotes demyelination and contributes to oligodendrocyte and axon damage. (B) Schematic of IL-6 signaling with potential modes of therapeutic inhibition. IL-6 can bind either to the membrane-bound (classic signaling) or soluble form (trans-signaling) of the IL-6R α receptor. IL-6 trans-signaling allows for the activation of cells that do not express the IL-6R α receptor. Classic signaling may be blocked by antibodies against IL-6 and IL-6R. Trans-signaling may be blocked by antibodies against IL-6R or the soluble form of glycoprotein 130 (sgp130). IL-6 signaling is mediated at the plasma membrane through the homodimerization of gp130, which activates the intracellular JAK-STAT and SHP2-MAPK signaling pathways. AQP4 = aquaporin-4; AQP4-IgG = aquaporin-4 immunoglobulin G; BBB = blood-brain barrier; CDC = complement-dependent cytotoxicity; CDCC = complement-dependent cellular cytotoxicity; D1-D3 = subdomain of IL-6Rα; IL-1β = interleukin-1β; IL-6 = interleukin-6; JAK/STAT = Janus kinase/signal transducers and activators of transcription; MAC = membrane attack complex; mAbs = monoclonal antibodies; MAPK = mitogen-activated protein kinase; NMOSD = neuromyelitis optica spectrum disorder; sgp130 = soluble glycoprotein 130; SHP2/MAPK = Src homology region 2 domain-containing phosphatase-2/mitogen-activated protein kinase; STAT3 = signal transducers and activators of transcription 3; Th = T helper cell; TNF-α = tumor necrosis factor α; Treg = regulatory T cell.