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• Correspondence on ‘Microglia activation in the presence of intact blood–brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus’ by Nikolopoulos et al
  Shuzo Sato
  Published on: 28 March 2024

• Published on: 28 March 2024

  Correspondence on ‘Microglia activation in the presence of intact blood–brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus’ by Nikolopoulos et al

  • Shuzo Sato, Associate Professor Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan

  I read with great interest the article by Nikolopoulos et al. [1]. This article explains a novel mechanism of disease development in neuropsychiatric systemic lupus erythematosus (NPSLE) using a lupus model mouse. NPSLE is common in SLE patients, with 6%–91% prevalence and it typically occurs in the early stages of SLE [2, 3]. However, the distinct pathogenesis of NPSLE is still unknown, owing in part to the difficulty of analyzing human subjects. Some lupus model mice develop neuropsychiatric disease through autoimmune mechanisms, making them a valuable disease model for human NPSLE [4]. In the central nervous system (CNS) manifestation of SLE, the hippocampus is the target organ for the activated immune system, causing neuropsychiatric symptoms such as depression, anxiety, and loss of memory [1, 5]. This article highlights that lupus model NZB/W-F1 mice exhibit activation of microglia in the early period of their life, prenephritic stage, resulting in defective hippocampal neurogenesis; this microglia activation leads to increased IL-6 and IL-18 production, which directly induce apoptosis of hippocampal neural stem cells, and finally impacts hippocampal-linked behavioral perturbations with the presence of an intact blood–brain barrier (BBB) [1]. This is a groundbreaking finding because most autoimmune processes associated with NPSLE were thought to begin with a disruption of the BBB [2, 3]. It is also worth noting that microglia could be a potential therapeutic target in...

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  I read with great interest the article by Nikolopoulos et al. [1]. This article explains a novel mechanism of disease development in neuropsychiatric systemic lupus erythematosus (NPSLE) using a lupus model mouse. NPSLE is common in SLE patients, with 6%–91% prevalence and it typically occurs in the early stages of SLE [2, 3]. However, the distinct pathogenesis of NPSLE is still unknown, owing in part to the difficulty of analyzing human subjects. Some lupus model mice develop neuropsychiatric disease through autoimmune mechanisms, making them a valuable disease model for human NPSLE [4]. In the central nervous system (CNS) manifestation of SLE, the hippocampus is the target organ for the activated immune system, causing neuropsychiatric symptoms such as depression, anxiety, and loss of memory [1, 5]. This article highlights that lupus model NZB/W-F1 mice exhibit activation of microglia in the early period of their life, prenephritic stage, resulting in defective hippocampal neurogenesis; this microglia activation leads to increased IL-6 and IL-18 production, which directly induce apoptosis of hippocampal neural stem cells, and finally impacts hippocampal-linked behavioral perturbations with the presence of an intact blood–brain barrier (BBB) [1]. This is a groundbreaking finding because most autoimmune processes associated with NPSLE were thought to begin with a disruption of the BBB [2, 3]. It is also worth noting that microglia could be a potential therapeutic target in NPSLE treatment. This report is very interesting, but I have a few concerns and would like to comment. First, I am wondering if the early immune dysfunction that causes behavioral changes is solely due to the autoimmune process in NZB/W-F1 mice. Previous studies have shown that NZB/W-F1 mice develop CNS lesions in the very late stage of their lives (no CNS lesions even at the age of 28 weeks) [6]. Furthermore, NZB mice, a parent of NZB/W-F1 mice, can develop neocortical ectopias, with a 40% incidence of altered behaviors [7]. It is unclear whether this abnormality is inherited in NZB/W-F1 mice, but neonatal abnormalities specific to NZB/W-F1 mice might be affected by microglia and the result of the study. In contrast, MRL/lpr mice developed CNS lesions at an early stage (occurs at 8 weeks of age) [6]. Given the nature of human NPSLE, it may be preferable to use MRL/lpr mice to investigate specific immune processes in CNS lesions in SLE. Second, NPSLE events typically occur within 1–2 years of onset; however, NP manifestations are quite diverse, including not only diffuse NPSLE but also focal symptoms with elusive onset timing; thus, early modification of the hippocampus may not be a hallmark of human NPSLE [3, 8]. Many autoantibodies or biomarkers have been linked to NPSLE pathogenesis, and disruption of BBB is thought to be a key mechanism in NPSLE development [1, 3, 8]. The condition of the CNS in preclinical NPSLE is poorly understood; however, only 12%–25% of patients developed neurological symptoms as an initial manifestation of SLE, even in juvenile-onset [9, 10]. This could imply that a small proportion of SLE patients have abnormal brain inflammation before the disease onset, even if cognitive dysfunction is commonly seen in SLE patients [2]. In any case, more research is needed to better understand the onset of NPSLE.
  Shuzo Sato
  Acknowledgment: The author is grateful to Enago (https://www.enago.jp) for the English language review.
  Ethics approval: Not applicable.

  REFERENCES
  1. Nikolopoulos D, Manolakou T, Polissidis A, et al. Microglia activation in the presence of intact blood-brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus. Ann Rheum Dis 2023;82:646–57.
  2. Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol 2019;15:137–52.
  3. Justiz-Vaillant AA, Gopaul D, Soodeen S, et al. Neuropsychiatric systemic lupus erythematosus: molecules involved in its imunopathogenesis, clinical features, and treatment. Molecules 2024;29:747.
  4. Richard ML, Gilkeson G. Mouse models of lupus: what they tell us and what they don't. Lupus Sci Med 2018;5:e000199.
  5. Small SA, Schobel SA, Buxton RB, et al. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 2011;12:585–601.
  6. Vogelweid CM, Johnson GC, Besch-Williford CL, et al. Inflammatory central nervous system disease in lupus-prone MRL/lpr mice: comparative histologic and immunohistochemical findings. J Neuroimmunol 1991;35:89–99.
  7. Schrott LM, Denenberg VH, Sherman GF, et al. Environmental enrichment, neocortical ectopias, and behavior in the autoimmune NZB mouse. Brain Res Dev Brain Res 1992;67:85–93.
  8. Sato S, Temmoku J, Fujita Y, et al. Autoantibodies associated with neuropsychiatric systemic lupus erythematosus: the quest for symptom-specific biomarkers. Fukushima J Med Sci 2020;66:1–9.
  9. Zhang Y, Han H, Chu L. Neuropsychiatric lupus erythematosus: future directions and challenges; a systematic review and survey. Clinics (Sao Paulo) 2020;75:e1515.
  10. Giani T, Smith EM, Al-Abadi E, et al. Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus: data from the UK juvenile-onset systemic lupus erythematosus cohort study. Lupus 2021;30:1955–65.

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  Conflict of Interest:
  None declared.

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