TNF and Increased Intracellular Iron Alter Macrophage Polarization to a Detrimental M1 Phenotype in the Injured Spinal Cord

Abstract

Macrophages and microglia can be polarized along a continuum toward a detrimental (M1) or a beneficial (M2) state in the injured CNS. Although phagocytosis of myelin in vitro promotes M2 polarization, macrophage/microglia in the injured spinal cord retain a predominantly M1 state that is detrimental to recovery. We have identified two factors that underlie this skewing toward M1 polarization in the injured CNS. We show that TNF prevents phagocytosis-mediated conversion from M1 to M2 cells in vitro and in vivo in spinal cord injury (SCI). Additionally, iron that accumulates in macrophages in SCI increases TNF expression and the appearance of a macrophage population with a proinflammatory mixed M1/M2 phenotype. In addition, transplantation experiments show that increased loading of M2 macrophages with iron induces a rapid switch from M2 to M1 phenotype. The combined effect of this favors predominant and prolonged M1 macrophage polarization that is detrimental to recovery after SCI.

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

“…Previous reports describe that microglia and macrophages express predominantly M1 markers for the first 2 weeks after SCI, whereas the expression of M2 signatures is scarce (Kigerl et al 2009;Kroner et al 2014). Here we first extended these observations using fluorescence-activated cell sorting analysis (FACS) to assess the temporal changes in expression of M1 (iNOS and CD16/32) and M2 (Arg1 and CD206) markers in microglia and macrophages for the first 4 weeks after spinal cord contusion injury in mice.…”

“…Microglia and macrophages display a predominantly pro-inflammatory/M1-like phenotype after SCI (Kigerl et al 2009;Kroner et al 2014). However, there is currently limited information about the factors that prevent these cells from acquiring a pro-repair M2-like phenotype after SCI.…”

“…This is likely related to the post-injury milieu of the spinal cord, since M2 macrophages rapidly lose such markers when transplanted into the contused spinal cord (Kigerl et al 2009). A recent report reveals that phagocytosis of erythrocytes, which occurs between day 7 and 14 after SCI, prevents macrophages to adopt a pro-repair/M2-like polarization via release of TNFα (Kroner et al 2014). …”

“…There is also evidence that TNFα can prevent the myelin phagocytosis-induced shift of M1 macrophages to M2 (Kroner et al 2014). However, the existance of mechanisms occuring at early stages after SCI that may hamper the convertion of microglia and macrophages from proinflammatory towards a phenotype that is more conducive for tissue repair has yet to be elucidated.…”

Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl‐p53 pathway

“…However, the expression of iron metabolism‐related proteins in M2 macrophages is different than that in M1 macrophages 1. Another study12, 13 showed that increasing levels of intracellular iron induced polarization of proinflammation macrophages. The results of these studies suggest that regulating iron concentration in macrophages may be a novel and effective strategy for cancer immunotherapy.…”