Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, China.
Department of Pediatric Rheumatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Front Immunol. 2022 Sep 20;13:926087. doi: 10.3389/fimmu.2022.926087. eCollection 2022.
PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disease caused by heterozygous gain-of-function mutation in PSTPIP1. As one of the PSTPIP1-associated inflammatory diseases (PAIDs), neutropenia is a distinct manifestation to separate PAMI syndrome from other PAIDs. This study aimed to investigate the potential role of neutrophils and inflammatory signatures in the pathogenesis of PAMI. PAMI neutrophils displayed markedly increased production of interleukin-1β (IL-1β) and IL-18 by enzyme linked immunosorbent assay (ELISA) assay and intracellular cytokine staining. ASC speck formation and lactic dehydrogenase (LDH) release are also increased in patient neutrophils suggesting elevated pyrin inflammasome activation followed by upregulated cell death in PAMI neutrophils. RNA sequencing result showed strong inflammatory signals in both nuclear-factor kappa B (NF-κB) pathway and interferon (IFN) pathway in patient neutrophils. This study highlighted that elevated proinflammatory cytokines IL-1β and IL-18, increased pyrin inflammasome activation, and upregulation of NF-κB and IFN signaling pathways in neutrophils play important roles in pathogenicity of PAMI syndrome.
PSTPIP1（脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白 1）相关髓系相关蛋白血症炎症（PAMI）综合征是一种由 PSTPIP1 杂合获得性功能突变引起的罕见自身炎症性疾病。作为 PSTPIP1 相关炎症性疾病（PAIDs）之一，中性粒细胞减少是将 PAMI 综合征与其他 PAIDs 区分开来的一个明显表现。本研究旨在探讨中性粒细胞和炎症特征在 PAMI 发病机制中的潜在作用。通过酶联免疫吸附试验（ELISA）和细胞内细胞因子染色，PAMI 中性粒细胞显示出明显增加的白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）产生。ASC 斑点形成和乳酸脱氢酶（LDH）释放也增加，表明 PAMI 中性粒细胞中 pyrin 炎性小体激活增加，随后细胞死亡上调。RNA 测序结果显示，患者中性粒细胞中的核因子 kappa B（NF-κB）途径和干扰素（IFN）途径均存在强烈的炎症信号。本研究强调，中性粒细胞中升高的促炎细胞因子 IL-1β和 IL-18、pyrin 炎性小体激活增加以及 NF-κB 和 IFN 信号通路的上调在 PAMI 综合征的发病机制中起重要作用。
