Distinct defects in early innate and late adaptive immune responses typify impaired fracture healing in diet-induced obesity.
Distinct defects in early innate and late adaptive immune responses typify impaired fracture healing in diet-induced obesity.
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DOI：
10.3389/fimmu.2023.1250309
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发表时间：
2023
影响因子：
7.3
通讯作者：
Elbarbary, Reyad A.
中科院分区：
文献类型：
--
作者：
Khajuria, Deepak Kumar;Reider, Irene;Kamal, Fadia;Norbury, Christopher C.;Elbarbary, Reyad A.
骨折是最常见的肌肉骨骼损伤，通过三个主要阶段愈合：炎症、修复和重塑。大约10%的骨折患者患有需要手术干预的愈合障碍，这给医疗体系带来了巨大的负担。随着代谢性疾病，如肥胖相关的高血糖/2型糖尿病(T2D)，愈合受损的比率增加，鉴于肥胖/T2D的发病率不断增加，这是一个日益令人担忧的问题。免疫细胞在骨折愈合中起着关键作用，而肥胖/T2D与免疫细胞功能缺陷有关。然而，关于骨痂中免疫细胞的化学计量比以及在愈合的不同阶段该免疫细胞如何变化的知识存在差距。在这里，我们使用互补的全局和单细胞技术来表征骨折骨痂中的免疫细胞谱系，并识别相对于未骨折的骨或骨髓，骨折骨痂中特异性丰富的群体。我们的分析确定了两个明显的免疫细胞渗入骨痂的波：第一波发生在骨折愈合的早期炎症阶段，第二波发生在晚期修复/早期重塑阶段，这与以前的报道一致。对每一波的综合分析显示，先天免疫细胞在炎症早期被激活，但在后来的阶段，它们恢复到稳态数量和激活水平。在先天免疫细胞中，活化的树突状细胞的不同亚群在炎性愈合血肿中特别丰富。与天然细胞不同，淋巴细胞，包括B和T细胞，在愈伤组织中主要在修复后期被丰富和激活。饮食诱导肥胖(DIO)小鼠是肥胖相关的高血糖和胰岛素抵抗的既定模型，患有多种愈合缺陷。我们的数据表明，DIO小鼠在炎症阶段表现出不受调节的先天免疫反应，在后期修复阶段所有淋巴细胞室都有缺陷。综上所述，我们的数据首次表征了在骨折愈合的两个不同阶段在骨痂中丰富/激活的免疫种群，并确定了DIO小鼠与愈合相关的免疫反应中的缺陷，这将促进未来针对骨折愈合受损的免疫调节疗法的发展。
Bone fractures, the most common musculoskeletal injuries, heal through three main phases: inflammatory, repair, and remodeling. Around 10% of fracture patients suffer from impaired healing that requires surgical intervention, a huge burden on the healthcare system. The rate of impaired healing increases with metabolic diseases such as obesity-associated hyperglycemia/type 2 diabetes (T2D), an increasing concern given the growing incidence of obesity/T2D. Immune cells play pivotal roles in fracture healing, and obesity/T2D is associated with defective immune-cell functions. However, there is a gap in knowledge regarding the stoichiometry of immune cells that populate the callus and how that population changes during different phases of healing. Here, we used complementary global and single-cell techniques to characterize the repertoire of immune cells in the fracture callus and to identify populations specifically enriched in the fracture callus relative to the unfractured bone or bone marrow. Our analyses identified two clear waves of immune-cell infiltration into the callus: the first wave occurs during the early inflammatory phase of fracture healing, while the second takes place during the late repair/early remodeling phase, which is consistent with previous publications. Comprehensive analysis of each wave revealed that innate immune cells were activated during the early inflammatory phase, but in later phases they returned to homeostatic numbers and activation levels. Of the innate immune cells, distinct subsets of activated dendritic cells were particularly enriched in the inflammatory healing hematoma. In contrast to innate cells, lymphocytes, including B and T cells, were enriched and activated in the callus primarily during the late repair phase. The Diet-Induced Obesity (DIO) mouse, an established model of obesity-associated hyperglycemia and insulin resistance, suffers from multiple healing defects. Our data demonstrate that DIO mice exhibit dysregulated innate immune responses during the inflammatory phase, and defects in all lymphocyte compartments during the late repair phase. Taken together, our data characterize, for the first time, immune populations that are enriched/activated in the callus during two distinct phases of fracture healing and identify defects in the healing-associated immune response in DIO mice, which will facilitate future development of immunomodulatory therapeutics for impaired fracture healing.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
影响因子：
7.3
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通讯作者：
Schmidt-Bleek, Katharina
影响因子：
7.3
作者：
Godwin JW;Pinto AR;Rosenthal NA
通讯作者：
Rosenthal NA
影响因子：
18.4
作者：
Böttcher JP;Reis e Sousa C
通讯作者：
Reis e Sousa C