“Tissue-repairing” blood-derived macrophages are essential for healing of the injured spinal cord: From skin-activated macrophages to infiltrating blood-derived cells?

Until recently, the local inflammation that occurs in response to spinal cord injury has received a negative reputation; overall, it was assumed to be one of the major causes of a vicious neurotoxic cycle that leads to impaired recovery following injury. This local inflammation involves both the activated tissue-resident microglia and monocyte-derived macrophages infiltrating from the blood. Ten years ago, we proposed that the blood-derived macrophages, reminiscent of “alternatively activated” macrophages (also known as tissue repairing, M2), are not spontaneously recruited in sufficient numbers to sites of injured central nervous system (CNS). We further demonstrated that their exogenous administration to the margins of injured spinal cord improved functional outcome. However, our suggestions evoked criticism, claiming that we were adding macrophages to a site that is already overwhelmed with inflammatory cells. Using experimental paradigms that enabled functional distinction between the resident and infiltrating cells, our most recent studies further corroborated our repair perception, showing that (a) infiltrating monocyte-derived macrophages are recruited following injury and localize to the margins of the lesion, unlike the activated resident microglia that are not compartmentalized, and (b) activated resident microglia and infiltrating monocyte-derived macrophages perform distinct roles; recruited blood-derived macrophages display an (IL-10-dependent) anti-inflammatory phenotype when they become co-localized with the glial scar. We further found that post-injury recruitment of blood monocytes is indeed suboptimal. Augmentation of the levels of naïve blood monocytes leads to their increased recruitment to the same zones that are the targets of the infiltrated endogenous monocytes, and they acquire the same anti-inflammatory activity, leading to improved recovery. Thus, boosting the levels of the relevant blood monocytes reinforces the body’s own repair mechanisms that, for reasons that are currently under investigation, are not optimally triggered within the critical post-injury period.