耶氏肺孢子虫肺炎 (PjP) 对免疫系统受损的个体构成严重风险，例如艾滋病毒/艾滋病患者或接受癌症免疫抑制治疗或实体器官移植的个体。严重的 PjP 会引发过度的肺部炎症，导致肺功能下降和随之而来的肺泡损伤，最终可能导致急性呼吸窘迫综合征。非 HIV 患者面临 30%-60% 的死亡率，强调需要更深入地了解 PjP 中的炎症反应。先前的研究强调肺孢子虫感染中的巨噬细胞，而忽略了中性粒细胞在组织损伤中的作用。因此，过分强调巨噬细胞导致对中性粒细胞和炎症反应的作用的不完全理解。在当前的研究中，我们对 PjP 小鼠替代模型的 RNAseq 研究揭示了其肺部 NLRP3 炎性体和 NETosis 细胞死亡途径的高度激活。免疫荧光染色证实感染鼠鼠的小鼠肺部存在中性粒细胞胞外陷阱（NET），验证了我们的发现。此外，当直接用 P. murina 刺激时，分离的中性粒细胞表现出 NETosis。分离的 NET 会损害鼠鼠的体外生存能力，这凸显了中性粒细胞在鼠鼠肺炎期间通过 NLRP3 炎性体组装和 NETosis 控制真菌生长和促进炎症的潜在作用。这些途径对于炎症和病原体消除至关重要，但存在不受控制的激活导致过度组织损伤和持续炎症的风险。这项开创性的研究首次确定了肺孢子虫感染期间 NET 和炎性小体的形成，为全面研究旨在减轻 PjP 患者肺损伤和提高生存率的治疗方法铺平了道路。 重要性 耶氏肺孢子虫肺炎 (PjP) 影响重症患者免疫力，例如艾滋病毒/艾滋病、癌症和器官移植患者。严重的 PjP 会引发肺部炎症、损害功能并可能导致急性呼吸窘迫综合征。非 HIV 个体面临 30%-60% 的死亡率，这凸显了深入了解 PjP 炎症反应的必要性。过去的研究主要集中在巨噬细胞控制肺孢子虫感染及其炎症方面，而中性粒细胞的作用通常被忽视。相比之下，我们在 P. murina 感染的小鼠肺部的发现显示，炎症过程中中性粒细胞参与，并且 NLRP3 炎性体和 NETosis 通路的表达增加。中性粒细胞胞外陷阱的检测进一步表明它们参与炎症过程。尽管有益于对抗感染，但不受调节的中性粒细胞激活对肺组织构成潜在威胁。了解肺孢子虫感染中中性粒细胞的行为对于控制有害反应和制定减少肺损伤的治疗方法至关重要，最终提高 PjP 患者的生存率。

Pneumocystis jirovecii pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30%-60% mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in Pneumocystis infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed neutrophil extracellular trap (NET) presence in the lungs of the P. murina-infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with P. murina. Isolated NETs compromised P. murina viability in vitro, highlighting the potential role of neutrophils in controlling fungal growth and promoting inflammation during P. murina pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during Pneumocystis infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.IMPORTANCEPneumocystis jirovecii pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30%-60% mortality rate, underscoring the need for deeper insight into PjP's inflammatory responses. Past research focused on macrophages in managing Pneumocystis infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in P. murina-infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues. Understanding the behavior of neutrophils in Pneumocystis infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.