Macrophages in spinal cord injury: Phenotypic and functional change from exposure to myelin debris

Abstract

Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury (SCI). It was reported that M2 macrophages were induced at 3–7 days after SCI but M2 markers were reduced or eliminated after 1 week. By contrast, M1 macrophage response is rapidly induced and then maintained at injured spinal cord. However, factors that modulate macrophage phenotype and function are poorly understood. We developed a model to distinguished bone marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion-related factors in injured spinal cord. Infiltrating BMDMs expressing higher Mac-2 and lower CX3CR1 migrate to the epicenter of injury, while microglia expressing lower Mac-2 but higher CX3CR1 distribute to the edges of lesion. Myelin debris at the lesion site switches BMDMs from M2 phenotype towards M1-like phenotype. Myelin debris activate ATP-binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading in vitro. However, this homeostatic mechanism in injured site is overwhelmed, leading to the development of foamy macrophages and lipid plaque in the lesion site. The persistence of these cells indicates a pro-inflammatory environment, associated with enhanced neurotoxicity and impaired wound healing. These foamy macrophages have poor capacity to phagocytose apoptotic neutrophils resulting in uningested neutrophils releasing their toxic contents and further tissue damage. In conclusion, these data demonstrate for the first time that myelin debris generated in injured spinal cord modulates macrophage activation. Lipid accumulation following macrophage phenotype switch contributes to SCI pathology.

Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury

“…Therefore, these results confirm that CCR2-expressing cells are increased in the ipsilateral ventral but not dorsal horn at POD 7 after SNT. Finally, to determine whether CCR2 RFP/+ monocytes have the ability to enter the spinal dorsal horn, we used a well-established mouse contusion model of spinal cord injury (SCI) (Wang et al, 2015) in CCR2 RFP/+ :CX3CR1 GFP/+ mice. Indeed, we found numerous CCR2 RFP/+ monocytes in spinal dorsal horn 7 days after SCI (Figure S2a).…”

Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization

“…55 Myelin debris may be an associated factor switching the macrophage phenotype from M2 to M1. 56 In addition, ROS are involved in the activation process of M1 macrophages partly by nuclear factor-kappa light-chain-enhancer of activated B cells (NF-kB) pathway. It still needs further study to understand how ROS, resulting from SCI, regulate the polarization of macrophages.…”

Melatonin improves functional recovery in female rats after acute spinal cord injury by modulating polarization of spinal microglial/macrophages

“…Accordingly, current study cannot differentiate whether the observed changes of polarization primarily occurred in which cell population. Future double‐staining study that use antibodies specific to microglia, such as P2Y12 and TMEM119(Bennett et al, ; Gu et al, ; Tatsumi et al, ; Wang et al, ) may allow identifying the specific cell population and quantifying the relative proportion of microglia versus macrophages that are modulated by melatonin treatment after SCI. Microglia/macrophages have been broadly categorized into two distinct states as either classically activated (M1) or alternatively activated (M2) state(Colonna & Butovsky, ; Wang et al, ).…”

“…Future double‐staining study that use antibodies specific to microglia, such as P2Y12 and TMEM119(Bennett et al, ; Gu et al, ; Tatsumi et al, ; Wang et al, ) may allow identifying the specific cell population and quantifying the relative proportion of microglia versus macrophages that are modulated by melatonin treatment after SCI. Microglia/macrophages have been broadly categorized into two distinct states as either classically activated (M1) or alternatively activated (M2) state(Colonna & Butovsky, ; Wang et al, ). Although this M1/M2 paradigm is helpful for conceptualizing microglia/macrophages activities in vitro, recent studies suggested that the spectrum of microglia/macrophages activation in vivo is likely a continuum of different phenotype states (Colonna & Butovsky, ; Morganti, Riparip, & Rosi, ).…”