淋巴管平滑肌瘤小鼠模型中子宫免疫微环境的炎症、功能和组成变化

Danielle S Stiene, Andrew R Osterburg, Lori B Corsarie, Nick R Balzarini, Mario Medvedovic, Michael T Borchers
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摘要

摘要淋巴管平滑肌瘤病是一种罕见的、以女性为主的肺部囊性疾病。在LAM中形成的囊肿以周围存在平滑肌样(LAMCore)细胞为特征。这些细胞在结节性硬化症复合体1或2 (TSC1/2)中携带突变,通过mTORC1途径驱动不受控制的增殖。LAMCore细胞起源于肺外。已发表的数据支持LAMCore细胞从子宫转移到肺功能破坏的子宫起源。假设发生免疫逃避,允许从子宫播散肺。这种逃避特别涉及功能失调的NK细胞,允许异常增殖和从组织迁移。单细胞RNA测序揭示了子宫特异性tsc2敲除小鼠LAM模型中子宫NK (uNK)和其他免疫细胞群中趋化因子、细胞因子蛋白和受体表达的变化。ELISA数据显示,老年tsc2基因敲除小鼠血清中多种促炎细胞因子浓度升高。流式细胞术、免疫组化和功能分析鉴定了tsc2敲除小鼠中uNK细胞的组成和功能缺陷。此外,NK细胞的消耗导致肺转移的发展增加。这些数据表明炎症反馈回路影响多种细胞类型,包括uNK细胞、巨噬细胞和中性粒细胞。这导致免疫细胞功能和组成的改变,从而允许LAMCore细胞从子宫组织转移,这可能为LAM的发展提供了一种新的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inflammatory, Functional, and Compositional Changes of the Uterine Immune Microenvironment in a Lymphangioleiomyomatosis Mouse Model.

Lymphangioleiomyomatosis (LAM) is a rare, female-dominated pulmonary cystic disease. Cysts that develop in LAM are characterized by the presence of smooth muscle-like (LAMCore) cells in the periphery. These cells harbor mutations in Tuberous Sclerosis Complex 1 or 2 (TSC1/2), driving uncontrolled proliferation through the mTORC1 pathway. LAMCore cells originate from an extrapulmonary source. Published data supports the uterine origin of LAMCore cells that metastasize from the uterus to precipitate pulmonary function destruction. Immune evasion is hypothesized to occur to allow seeding of the lungs from the uterus. This evasion specifically involves dysfunctional NK cells to allow aberrant proliferation and migration from the tissue. Single-cell RNA sequencing revealed changes in chemokine and cytokine protein and receptor expression in uterine NK (uNK) and other immune cell populations in a uterine-specific Tsc2-knockout mouse model of LAM. ELISA data revealed increased concentrations of multiple pro-inflammatory cytokines in the sera of aged Tsc2-knockout mice. Flow cytometry, IHC, and functional assays identified compositional and functional insufficiencies of the uNK cells in Tsc2-knockout mice. Furthermore, depletion of NK cells led to the increased development of pulmonary metastases. These data suggest an inflammatory feedback loop affecting multiple cell types including uNK cells, macrophages, and neutrophils. This leads to alterations in immune cell function and composition which allow for LAMCore cell metastasis from the uterine tissue, which may provide a novel mechanism for LAM development.

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