Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord

By Kristina A. Kigerl, J. Gensel, Daniel P. Ankeny, Jessica K. Alexander, Dustin J. Donnelly, P. Popovich. Journal of Neuroscience, 2009

1,994 citations recorded by the source corpus.

Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., “classically activated” proinflammatory (M1) or “alternatively activated” anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or “alternatively” activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

Subfields: Cellular and Molecular Neuroscience, Neurology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/536cb1a440990f709717735089a1968fe53ad500

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Neurology

In Pathology and Forensic Medicine

Citations in the corpus

Microglia in the TBI Brain: The Good, The Bad, And The Dysregulated (2015, background): “…majority of microglia and recruited macrophages at the site of injury have mixed M1- and M2-like activation profiles, but that the M2-like response is short-lived and there is a phenotypic shift towards an M1-like dominant response within one week of injury (Hu et al., 2012; Kigerl et al., 2009).”
Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury (2011, background): “We then compare the PNI-induced inflammatory response with that elicited by SCI. Responses extrinsic to the neuron after nerve injury Injury elicits a vigorous response from non-neuronal cells in the peripheral nerve, especially in the distal nerve stump (Figure 1).”
Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine (2012, background): “These cells have been shown to possess a predominantly pro-inflammatory phenotype following injury, resulting in a microenvironment that is cytotoxic and propagates tissue damage and scar tissue deposition [128].”
Recruitment of Beneficial M2 Macrophages to Injured Spinal Cord Is Orchestrated by Remote Brain Choroid Plexus (2013, positive): “In addition, blood-derived macrophages contribute to CNS repair, in part by displaying resolving M2 phenotype (Kigerl et al., 2009; Rapalino et al., 1998; Shechter et al., 2009; Yin et al., 2006).”
Microglial M1/M2 polarization and metabolic states (2016, background): “Based upon the temporal expression of M1- and M2-related factors in a mouse spinal cord injury model, Kigerl et al. (2009) examined the effect of conditioned media from bone marrow-derived macrophages on dorsal root ganglion cell survival and neurite outgrowth.”
Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia (2012, background): “The dualistic roles of distinctly polarized macrophage populations have been reported in several central nervous system diseases, including multiple sclerosis(7) and spinal cord injury.(2) Recently, the concept of microglial M1 and M2 phenotypes also has entered the field of stroke research.”
The Role of Macrophage Phenotype in Vascularization of Tissue Engineering Scaffolds (2014, positive): “Since then, these “M2” macrophages, named following the helper T cell nomenclature (Th1/Th2) and in contrast to pro-inflammatory “M1” macrophages, have been associated with the resolution of wound healing in vivo in chronic leg ulcers [7], atherosclerotic lesions [8], traumatic spinal cord injury [9”
TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. (2014, positive): “…and microglia phagocytose myelin and other tissue debris in the first 2 weeks after spinal cord contusion injury, the environment of the injured spinal cord favors M1 polarization as shown by our FACS analysis described above (Figure 1), as well as in an earlier report (Kigerl et al., 2009).”
Macrophage activation and its role in repair and pathology after spinal cord injury. (2015, background): “A similar mixed M1 and M2a macrophage response occurs early after SCI (Kigerl et al., 2009).”
Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. (2016, background): “CNS injury, activated microglia and macrophages at the lesion sites mostly express M2 signature genes, while they predominately express M1 genes by approximately 1 week after injury (Kigerl et al., 2009; Perego et al., 2011; Wang et al., 2013a).”
Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis (2014, positive): “Depending on themilieu in which they become activated, microglia differentiate into inflammatory (M1) and antiinflammatory (M2) effector cells with the potential to kill invading pathogens or neurons (M1), promote tissue repair, or dampen the immune response (M2) (Kigerl et al., 2009).”
Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. (2012, positive): “This is further complicated by the influence of infiltrating blood-borne macrophages of M1 or M2 phenotype and other infiltrating cells following CNS injury (Kigerl et al., 2009).”