**6. The M1/M2 continuum in TBI**

Monocyte/macrophages display different phenotypes depending on the cellular microenvironment. Classical macrophages, called M1 macrophages, specialize in promoting inflammation and phagocytosing pathogens. The second class of

macrophages, called M2 macrophages, serves to promote tissue recovery [45]. Macrophages are a critical part of the tissue repair process following injury, but these cells can be either helpful or damaging depending on M1/2 status. Following TBI, macrophage polarization toward the M1 phenotype has been associated with neurodegeneration, while polarization toward the M2 phenotype has been shown to reduce oxidative stress [46]. However, these classes are not absolute—macrophages respond to their cellular environment to become more or less M1/2, existing on a continuum with M1 and M2 subcharacteristics at either end [45]. The varied expression of M1 pro-inflammatory vs. M2 pro-recovery traits can be a critical factor in recovery during the peripheral-derived inflammatory response to TBI.
