Pro-inflammatory polarization primes Macrophages to transition into a distinct M2-like phenotype in response to IL-4

Tissue repair is largely regulated by diverse M phi populations whose functions are timing- and context-dependent. The early phase of healing is dominated by pro-inflammatory M phi s, 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 M phi s may originate directly from circulating monocytes or from phenotypic switching of pre-existing M1 M phi s 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 M phi behavior. This study investigated the influence of prior M1 activation on human M phi polarization to an M2 phenotype in response to IL-4 treatment in vitro. Compared to unactivated (M0) M phi s, M1 M phi s up-regulated several receptors that promote the M2 phenotype, including the primary receptor for IL-4. M1 M phi s 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 M phi response to treatment with IL-4, generating an M2-like phenotype with a distinct gene and protein expression signature compared to M2 M phi s prepared directly from M0 M phi s. Functionally, compared to M0-derived M2 M phi s, M1-derived M2 M phi s demonstrated increased migratory response to SDF-1 alpha, and conditioned media from these M phi s promoted increased migration of endothelial cells in transwell assays, although other common M phi-associated functions such as phagocytosis were not affected by prior polarization state. In summary, M1 polarization appears to prime M phi s 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.

Automated summary

This study found that prior M1 activation can influence human Mφ polarization to an M2 phenotype, leading to increased expression of some genes and proteins, decreased expression of others, and functional differences. This suggests the importance of prior M1 activation in regulating subsequent M2 behavior.