Harnessing monocyte‐derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’

Abstract

The central nervous system (CNS) tissues, including the brain, the eye, and the spinal cord, are immune-privileged, secluded from the circulation by a complex of barriers, and equipped with their own myeloid cell population, the resident microglia. Based on the classical perspective of immune-brain interactions and on the contribution of such interactions to the progression of multiple sclerosis, an autoimmune inflammatory disease of the CNS, infiltrating macrophages were traditionally viewed as an enemy of the nervous system. However, over the past two decades, research has revealed the pivotal role of monocyte-derived macrophages in CNS repair, and opened up a new era in understanding and treating CNS pathologies. Here, we gather current knowledge regarding macrophage broad spectrum of activities in the CNS, whose two poles correspond to the classical pro-inflammatory M1 and the 'alternatively-activated' M2 cells previously described in various non-CNS pathologies, and their diverse, multifunctional contribution in various neurological conditions, ranging from acute traumas to neurodegenerative disorders, and autoimmune diseases. The diverse functions are manifested by induction and resolution of inflammation as well as their involvement in neural tissue regeneration and renewal, matrix remodelling, debris clearance, and angiogenesis. A special focus is devoted to current evidence suggesting that resident microglia and infiltrating monocyte-derived macrophages are functionally non-redundant cell types. Taken together, these recent advances reveal a dramatic therapeutic opportunity for controlled harnessing of macrophages for repair of the damaged CNS following acute insults, in neurodegenerative conditions, and in psychiatric disorders.

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

“…Recent reports indicate that the recruitment of inflammatory Ly6C high monocytes and their macrophage or DC progeny reflects the changing needs of the affected tissue along the course of inflammation, which includes cytokine production, Ag presentation, and phagocytosis of cellular debris (12,13,35,36). In the CNS, functional macrophage heterogeneity has been demonstrated in several models of autoimmune pathology as well as in neurodegenerative and infectious diseases (19,26,27,36,37), but the precise role of the recruited mononuclear cell subsets in cerebral toxoplasmosis remains to be addressed. Subsequently, the availability of new surface markers and fate mapping led to a paradigm shift describing the behavior of distinct monocyte-derived macrophages and their difference to tissueresident mononuclear cells (26,33,38,39).…”

“…The adaptive immune responses in the CNS have been extensively investigated, describing an important contribution to the local parasite control (22)(23)(24)(25). Besides, several studies have highlighted the function and phenotype of certain mononuclear cells such as microglia, brain DCs, and macrophages upon cerebral toxoplasmosis; however, the role of recruited newly described myeloid cell subpopulations remains undefined (19,26,27).…”

Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory

“…Chronic M1 macrophage activation promotes tissue damage in neurodegenerative disorders, arthritis, and autoimmune diseases (12,15,16). Although necessary for the initial stages of tissue repair, excessive M1 activation inhibits the healing of damaged tissue through excessive matrix degradation and inhibition of tissue regeneration (17,18).…”

The Peripheral Network between Oxidative Stress and Inflammation in Multiple Sclerosis

“…CD 14+ IL 10+ are cells with M2 functional phenotype (43,44) capable of tuning the immune responses also by releasing IL-10 crucial in down-modulating adaptive and innate immune responses (45)(46)(47).…”