School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.
J Leukoc Biol. 2022 May;111(5):989-1000. doi: 10.1002/JLB.3A0520-338R. Epub 2021 Oct 13.
Tissue repair is largely regulated by diverse Mϕ populations whose functions are timing- and context-dependent. The early phase of healing is dominated by pro-inflammatory 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.
组织修复主要受多种巨噬细胞（Mϕ）群体的调节，其功能具有时间和上下文依赖性。愈合的早期阶段由促炎巨噬细胞（也称为 M1）主导，随后出现一种独特而多样的群体，统称为 M2。M2 群体的多样性程度尚不清楚。M2 Mϕ 可能直接来源于循环单核细胞，也可能来源于损伤部位内预先存在的 M1 Mϕ 的表型转换。这些群体之间的差异尚未被充分理解，但对理解和治疗以 M2 激活不足为特征的病理学具有重要意义，例如慢性伤口，其也表现出 M1 Mϕ 行为的减弱。本研究调查了先前 M1 激活对人 Mϕ 向 IL-4 体外治疗的 M2 表型极化的影响。与未激活（M0）的 Mϕ 相比，M1 Mϕ 上调了几种促进 M2 表型的受体，包括 IL-4 的主要受体。M1 Mϕ 还对较低剂量的 IL-4 （包括低至 10 pg/mL）上调 M2 标志物，并加速 STAT6 磷酸化。然而，M1 激活似乎也改变了 Mϕ 对 IL-4 治疗的反应，产生了一种与直接从 M0 Mϕ 制备的 M2 Mϕ 具有明显不同的基因和蛋白质表达特征的 M2 样表型。在功能上，与 M0 衍生的 M2 Mϕ 相比，M1 衍生的 M2 Mϕ 对 SDF-1α 的迁移反应增强，并且这些 Mϕ 的条件培养基在 Transwell 测定中促进了内皮细胞的迁移增加，尽管吞噬等其他常见的 Mϕ 相关功能不受先前极化状态的影响。总之，M1 极化似乎使 Mϕ 对 IL4 产生反应而转变为独特的 M2 表型，导致一些基因和蛋白质的表达增加，而另一些基因和蛋白质的表达减少，以及功能差异。总之，这些发现表明先前 M1 激活在调节随后的 M2 行为中的重要性，并表明纠正 M1 行为可能是功能失调的 M2 激活的治疗靶点。
