Bone Marrow-Derived Monocytes Drive the Inflammatory Microenvironment in Local and Remote Regions after Thoracic Spinal Cord Injury

Abstract

Spinal cord injury (SCI) produces a toxic inflammatory microenvironment that negatively affects plasticity and recovery. Recently, we showed glial activation and peripheral myeloid cell infiltration extending beyond the epicenter through the remote lumbar cord after thoracic SCI. The presence and role of infiltrating monocytes is important, especially in the lumbar cord where locomotor central pattern generators are housed. Therefore, we compared the inflammatory profile of resident microglia and peripheral myeloid cells after SCI. Bone marrow chimeras received midthoracic contusive SCI, and trafficking was determined 1-7 days later. Fluorescence-activated cell (FAC) sorting showed similar infiltration timing of both neutrophils and macrophages in epicenter and lumbar regions. While neutrophil numbers were attenuated by day 3, macrophages remained unchanged at day 7, suggesting that macrophages have important long-term influence on the microenvironment. Nanostring gene array identified a strong proinflammatory profile of infiltrating macrophages relative to microglia at both epicenter and lumbar sites. Macrophages had elevated expression of inflammatory cytokines (IL-1β, IFNγ), chemokines (CCL2, CXCL2), mediators (COX-1, MMP-9), and receptors (CCR2, Ly6C), and decreased expression of growth promoting genes (GDNF, BDNF). Importantly, lumbar macrophages had elevated expression of active trafficking genes (CCR2, l-selectin, MMP-9) compared with epicenter macrophages. Further, acute rehabilitation exacerbated the inflammatory profile of infiltrated macrophages in the lumbar cord. Such high inflammatory potential and negative response to rehabilitation of infiltrating macrophages within lumbar locomotor central pattern generators likely impedes activity-dependent recovery. Therefore, limiting active trafficking of macrophages into the lumbar cord identifies a novel target for SCI therapies to improve locomotion.

Location of neonatal microglia drives small extracellular vesicles content and biological functions in vitro

“…produced by bone marrow-derived monocytes/macrophages [9,10,71,72] reinforcing the hypothesis of a different origin of the SpC-M than the one present in the brain. Furthermore, functional biological tests with DRGs cell lines showed that sEVs derived from microglial cultures stimulate neurite outgrowth, with slight variations.…”

“…By contrast, pathways associated with SpC‐M's sEVs show correlation to inflammatory processes which correlate also with the cellular–based proteome of SpC‐M detected in the present study. In addition, proteins identified in SpC‐M sEVs (Cfh, GPR77, C4a, Lgal3bp, Lgals1, C1S and Cfhr1) are also produced by bone marrow‐derived monocytes/macrophages [9,10,71,72] reinforcing the hypothesis of a different origin of the SpC‐M than the one present in the brain. Furthermore, functional biological tests with DRGs cell lines showed that sEVs derived from microglial cultures stimulate neurite outgrowth, with slight variations.…”

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

“…Under pathological conditions, such as those associated to neurodegenerative disorders (Gonzalez and Pacheco, 2014), or CNS injury (Wattananit et al, 2016;Olingy et al, 2017;Norden et al, 2019; peripheral monocytes play an important role contributing to neuroinflammation. For instance, using a rat model of peripheral inflammation it has been shown that monocytes depletion, mediated by the peripheral administration of clodronate, mitigates the production of inflammatory mediators and microglial activation without affecting dopaminergic neuronal survival (Xie et al, 2017).…”

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