Dissecting the Damaging Versus Regenerative Roles of CNS Macrophages: Implications for the Use of Immunomodulatory Therapeutics

Abstract

Injury in the CNS is associated with a rapid and robust innate immune response consisting of macrophages derived from circulating monocytes and endogenous microglia. These cells’ function is to survey the cellular environment, phagocytose dead cells or debris, present antigens to T lymphocytes and secrete factors that modify neural and immune responses. Whether macrophages exacerbate damage or contribute to regeneration in the CNS is of great debate. This has major implications for the use of immunomodulatory therapies for the treatment of neurodegenerative diseases. Multiple sclerosis (MS) is one such disease where macrophages have been implicated in both inducing damage (demyelination) and regeneration (remyelination) in the CNS [1]. Although neuropathological observations of increased macrophage numbers or changes in macrophage morphology have traditionally been assumed to reflect a causal association with CNS damage, more recent studies using functional and expression profiling have shown that these responses can be indicative of a regenerative role for macrophages (described in detail in the section ‘Regenerative properties of macrophages’). This article reviews the experimental evidence for the damaging and regenerative properties of macrophages in the CNS, with implications for the use of immuno modulatory therapies and the development of novel therapeutic strategies for MS. Damaging properties of macrophages Traditionally, macrophage activation has been viewed as deleterious for the survival and function of neural cells. Indeed, interfering with macrophage activation by administration of the antibiotic minocycline improves recovery from experimental spinal cord injury, traumatic brain