Pro-inflammatory polarization primes Macrophages to transition into a distinct M2-like phenotype in response to IL-4.
Pro-inflammatory polarization primes Macrophages to transition into a distinct M2-like phenotype in response to IL-4.
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DOI：
10.1002/jlb.3a0520-338r
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发表时间：
2022-05
影响因子：
5.5
通讯作者：
Spiller, Kara L.
中科院分区：
文献类型：
--
作者：
O'Brien, Erin M.;Spiller, Kara L.
组织修复在很大程度上是由不同的M细胞群调节的，其功能是时间和环境依赖性的。愈合的早期阶段由促炎性M β细胞（也称为M1）主导，随后出现了一个独特而多样的群体，统称为M2。M2种群的多样性程度尚不清楚。M2 M可能直接来源于循环单核细胞或来源于损伤部位内预先存在的M1 M的表型转换。这些组之间的差异知之甚少，但对理解和治疗以M2活化缺陷为特征的病理学（如慢性伤口）具有重要意义，这些病理学也表现出M1 M活化行为减弱。本研究调查了在体外，预先激活M1对响应于IL-4处理的人M β极化至M2表型的影响。与未活化的（M0）M β相比，M1 M β上调了促进M2表型的几种受体，包括IL-4的主要受体。M1 M β细胞还响应于较低剂量的IL-4（包括低至10 pg/mL的剂量）上调M2标志物，并加速STAT 6磷酸化。然而，M1活化似乎也改变了M β对IL-4处理的反应，与直接从M0 M β制备的M2 M β相比，产生了具有不同基因和蛋白表达特征的M2样表型。在功能上，与M0衍生的M2 M β细胞相比，M1衍生的M2 M β细胞对SDF-1α的迁移反应增加，在transwell试验中，这些M β细胞的条件培养基促进内皮细胞迁移增加，尽管其他常见的M β相关功能（如吞噬作用）不受先前极化状态的影响。总之，M1极化似乎引发M β细胞响应于IL 4而转变为不同的M2表型，这导致一些基因和蛋白质的表达增加和其他基因和蛋白质的表达减少以及功能差异。总之，这些研究结果表明，在调节随后的M2行为的重要性，并建议，纠正M1的行为可能是一个治疗目标，在功能失调的M2激活。
Tissue repair is largely regulated by diverse Mϕ populations whose functions are timing- and context-dependent. The early phase of healing is dominated by proinflammatory Mϕs, also known as M1, followed by the emergence of a distinct and diverse population that is collectively referred to as M2. The extent of the diversity of the M2 population is unknown. M2 Mϕs may originate directly from circulating monocytes or from phenotypic switching of pre-existing M1 Mϕs within the site of injury. The differences between these groups are poorly understood, but have major implications for understanding and treating pathologies characterized by deficient M2 activation, such as chronic wounds, which also exhibit diminished M1 Mϕ behavior. This study investigated the influence of prior M1 activation on human Mϕ polarization to an M2 phenotype in response to IL-4 treatment in vitro. Compared to unactivated (M0) Mϕs, M1 Mϕs up-regulated several receptors that promote the M2 phenotype, including the primary receptor for IL-4. M1 Mϕs also up-regulated M2 markers in response to lower doses of IL-4, including doses as low as 10 pg/mL, and accelerated STAT6 phosphorylation. However, M1 activation appeared to also change the Mϕ response to treatment with IL-4, generating an M2-like phenotype with a distinct gene and protein expression signature compared to M2 Mϕs prepared directly from M0 Mϕs. Functionally, compared to M0-derived M2 Mϕs, M1-derived M2 Mϕs demonstrated increased migratory response to SDF-1α, and conditioned media from these Mϕs promoted increased migration of endothelial cells in transwell assays, although other common Mϕ-associated functions such as phagocytosis were not affected by prior polarization state. In summary, M1 polarization appears to prime Mϕs to transition into a distinct M2 phenotype in response to IL4, which leads to increased expression of some genes and proteins and decreased expression of others, as well as functional differences. Together, these findings indicate the importance of prior M1 activation in regulating subsequent M2 behavior, and suggest that correcting M1 behavior may be a therapeutic target in dysfunctional M2 activation.