Insights into the role of neutrophils in neuropsychiatric systemic lupus erythematosus: Current understanding and future directions

Abstract

Central nervous system (CNS) involvement of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a major and debilitating manifestation of the disease. While patients with SLE mostly complain of common neuropsychological symptoms such headache and mild mood disorders that may not even be technically attributed to SLE, many SLE patients present with life-threatening NPSLE syndromes such as cerebrovascular disease, seizures and psychosis that are equally challenging in terms of early diagnosis and therapy. While we are just beginning to unravel some mysteries behind the immunologic basis of NPSLE, advancements in the mechanistic understanding of the complex pathogenic processes of NPSLE have been emerging through recent murine and human studies. The pathogenic pathways implicated in NPSLE are multifarious and various immune effectors such as cell-mediated inflammation, autoantibodies and cytokines including type I interferons have been found to act in concert with the disruption of the blood-brain barrier (BBB) and other neurovascular interfaces. Beyond antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. Activated neutrophils have been recognized to be involved in ischemic and infective processes in the CNS by releasing neutrophil extracellular traps (NETs), matrix metalloproteinase-9 and proinflammatory cytokines. In the context of NPSLE, these mechanisms contribute to BBB disruption, neuroinflammation and externalization of modified proteins on NETs that serve as autoantigens. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low-density neutrophils (LDNs) or low-density granulocytes. LDNs are a proinflammatory subset of neutrophils that are increased with SLE disease activity and are primed to undergo NETosis and release cytokines such as interferon-α and tumor necrosis factor. This review discusses the immunopathogenesis of NPSLE with a focus on neutrophils as a core mediator of the disease and potential target for translational research in NPSLE.

Keywords: bloodbrain barrier; extracellular traps; neuropsychiatric systemic lupus erythematosus; neutrophils; systemic lupus erythematosus.

Figure 1

Pathogenic mechanism of BBB disruption. Blood-brain barrier disruption in NPSLE has been found to be related to various distinct but potentially complementary pathways involving neutrophils and their cellular products. Adhesion molecules ICAM-1 and E-selectin present on the vasculature of the brain promote neutrophil arrest and adhesion, leading to recruitment of pathogenic neutrophils to the BBB. These neutrophils produce NETs which cause direct endothelial damage and serve as a source of antigens for the development of autoantibodies including aPL and anti-NR2A/B antibodies. These autoantibodies can further aggravate endothelial damage and promote endothelial activation. The downstream effect is increased permeability of the BBB and secretion of pro-inflammatory cytokines including IL-6 and IL-8.

Figure 2

Proposed mechanism for NPSLE. Insults to the BBB allow penetration of the central nervous system by neutrophils and other inflammatory mediators. Cognitive deficits and other neuropsychiatric manifestations are caused by cytokines such as type I IFNs, anti-neuronal autoantibodies including anti-NR2A/B and matrix metalloproteinase-9 instigating neuronal damage and induction of apoptosis. C5a complement fragments are chemotactic and promote migration of immune cells including neutrophils into the CNS, an effect amplified by the ability of C5a to enhance NETosis and increase permeability of the BBB. C5a also exerts direct neurotoxic effects, contributing to further neuropsychiatric insults in NPSLE.