蛋白介導CD11c高表達巨噬細胞的預編程抗炎表型保護過敏性哮喘

2023年12月，重慶醫科大學檢驗醫學院檢驗醫學診斷教育部重點實驗室，重慶400016;遵義市第一人民醫院(遵義醫科大學第三附屬醫院)檢驗醫學科(Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China；Department of Laboratory Medicine, The First People’s Hospital of Zunyi City (The Third Afliated Hospital of Zunyi Medical University)) Bingyan Wu老師研究團隊在《Journal of Translational Medicine》上發表論文：

 “The preprogrammed anti-inflammatory phenotypes of CD11chigh macrophages by Streptococcus pneumoniae aminopeptidase N safeguard from allergic asthma"

“肺炎鏈球菌氨基肽酶N介導CD11c高表達巨噬細胞的預編程抗炎表型保護過敏性哮喘"

Abstract：

Background: Early microbial exposure is associate with protective allergic asthma. We have previously demonstrated that Streptococcus pneumoniae aminopeptidase N (PepN), one of the pneumococcal components, inhibits ovalbumin (OVA) -induced airway inflammation in murine models of allergic asthma, but the underlying mechanism was incompletely determined.

Methods: BALB/c mice were pretreated with the PepN protein and exposed intranasally to HDM allergen. The anti-inflammatory mechanisms were investigated using depletion and adoptive transfer experiments as well as transcriptome analysis and isolated lung CD11chigh macrophages.

Results: We found pretreatment of mice with PepN promoted the proliferation of lung-resident F4/80+CD11chigh macrophages in situ but also mobilized bone marrow monocytes to infiltrate lung tissue that were then transformed into CD11high macrophages. PepN pre-programmed the macrophages during maturation to an anti-inflammatory phenotype by shaping the metabolic preference for oxidative phosphorylation (OXPHOS) and also inhibited the inflammatory response of macrophages by activating AMP-activated protein kinase. Furthermore, PepN treated macrophages also exhibited high-level costimulatory signaling molecules which directed the differentiation into Treg.

Conclusion: Our results demonstrated that the expansion of CD11chigh macrophages in lungs and the OXPHOS metabolic bias of macrophages are associated with reduced allergic airway inflammation after PepN exposure, which paves the way for its application in preventing allergic asthma.

摘要：

背景:早期微生物暴露與保護性過敏性哮喘有關。研究人員之前已經證明肺炎鏈球菌氨基肽酶N (PepN)是一種肺炎球菌成分，在小鼠過敏性哮喘模型中抑制卵清蛋白(OVA)誘導的氣道炎癥，但其潛在機制尚不確定。

方法:用PepN蛋白預處理BALB/c小鼠，鼻內暴露HDM變應原。通過耗竭和過繼轉移實驗以及轉錄組分析和分離的肺cd11高巨噬細胞來研究其抗炎機制。

結果:研究人員發現用PepN預處理小鼠可促進肺內F4/80+ cd11高巨噬細胞的原位增殖，并可動員骨髓單核細胞浸潤肺組織，然后轉化為cd11高巨噬細胞。PepN通過塑造氧化磷酸化(OXPHOS)的代謝偏好，在巨噬細胞成熟過程中預編程為抗炎表型，并通過激活amp激活的蛋白激酶抑制巨噬細胞的炎癥反應。此外，PepN處理的巨噬細胞也表現出高水平的共刺激信號分子，引導分化為Treg。

結論:研究人員的研究結果表明，肺中cd11高的巨噬細胞的擴張和巨噬細胞的OXPHOS代謝偏倚與PepN暴露后過敏性氣道炎癥的減少有關，這為其在預防過敏性哮喘中的應用奠定了基礎。

該論文中，6-8周齡C57BL/6 J小鼠BMDMs（骨髓源性巨噬細胞）的體外培養是使用Ausbian特級胎牛血清完成的。