Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

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Corsi-Zuelli, Fabiana ; Henriques Schneider, Ayda ; Santos-Silva, Thamyris ; Marcelino Loureiro, Camila ; Shuhama, Rosana ; Rossi Menezes, Paulo ; Silveira Guimaraes, Francisco ; Villela Gomes, Felipe ; Queiroz Cunha, Fernando ; Louzada, Paulo ; Marta Del-Ben, Cristina

• Tipo de documento: Artigo Científico
• Fonte: TRANSLATIONAL PSYCHIATRY; v. 12, n. 1, p. 11-pg., 2022-12-26.

Resumo

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/11167-3 - Interações genético-ambientais na Esquizofrenia e outros transtornos psicóticos
• Beneficiário: Rosana Shuhama
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
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• Beneficiário: Felipe Villela Gomes
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 12/05178-0 - Esquizofrenia e outros transtornos psicóticos: determinantes sociais e biológicos
• Beneficiário: Paulo Rossi Menezes
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/19190-0 - Papel das NETs como moduladoras da osteoclastogênese na Artrite Reumatoide
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• Modalidade de apoio: Bolsas no Brasil - Doutorado
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• Beneficiário: Fabiana Maria das Graças Corsi Zuelli
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/07448-3 - Imunofenotipagem de pacientes com psicose imunologicamente ativos e o papel da interleucina-6
• Beneficiário: Fabiana Maria das Graças Corsi Zuelli
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 20/15752-1 - Uso de cannabis, trauma na infância e variantes endocanabinóides e glutamatérgicas: risco de psicose
• Beneficiário: Camila Marcelino Loureiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/24304-0 - Novas perspectivas no emprego de fármacos que modificam neurotransmissores atípicos no tratamento de transtornos neuropsiquiátricos
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• Modalidade de apoio: Auxílio à Pesquisa - Temático