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.

The double‐edged role of neutrophil heterogeneity in inflammatory diseases and cancers

“…The study of neutrophils, especially neutrophil heterogeneity, is of great momentousness in the field of cardiovascular and cerebrovascular diseases. 201 , 202 , 203 The normal‐density neutrophils (NDNs) and LDN subpopulations in the peripheral blood of patients with hypertension‐associated chronic inflammation exhibited higher levels of Na + influx and ROS, along with lower levels of apoptosis and stronger proinflammatory ability, thereby promoting the chronic inflammatory response associated with hypertension. 204 Some research teams identified that Ly6G + SiglecF + (Myc + NFϰB + ) neutrophils served as proinflammatory cells in the progression of myocardial infarction (MI).…”

Insights into the pathogenic role of neutrophils in systemic lupus erythematosus

“…Systemic tissue injury is a major characteristic of SLE [50], and neutrophils are involved in damage caused in the kidneys [15], skin [15], placenta [51 ▪ ], and nervous system [52 ▪ ]. Mechanistically, neutrophils recruited by local chemokines and immune complexes can produce tissue-damaging molecules such as granzymes and reactive oxygen species (ROS) [10 ▪ ].…”

Differences between human male and female neutrophils in mRNA, translation efficiency, protein, and phosphoprotein profiles

“…Polymorphonuclear cells (neutrophils) are the most abundant circulating immune cell in humans, representing 50–70% of all leukocytes [ 1 , 2 ], are an important component of the innate immune system [ 3 ], and are part of the first line of defense against microorganisms [ 4 ]. Neutrophils also have a role in tissue homeostasis, but aberrant activation and persistence can contribute to inflammation and the progression of some disease conditions [ 3 ], including acute respiratory distress syndrome (ARDS) [ 5 ], rheumatoid arthritis (RA) [ 6 ], and many other disorders [ 7 – 10 ].…”