Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury

Abstract

Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

“…As a marker of A1 astrocytes, the expression of C3 began to be signi cantly upregulated at 7 dpi and strengthened in the following 28 dpi. Therefore, we conclude that neurotoxic microglia and astrocytes are activated in succession in the acute and subacute phases of SCI, and both of them are involved in secondary neuroin ammation, which is consistent with previous reports [33,34]. In view of the fact that little is known about the activation of M1 and A1, we tried to identify the underlying mechanism through RNAseq analysis.…”

Beyond Activation: Characterizing Microglial Functional Phenotypes

“…Despite being known as a homeostatic marker [ 45 ], several studies have shown a stable expression of TMEM119 also in response to injury and inflammatory conditions. In spinal cord injuries, TMEM119-positive cells also stained positive for typical activation markers, such as MHCII and CD68, detecting a pro-inflammatory activation of microglial cells [ 46 ]. However, necrotic lesions of cerebral infarctions and demyelinating lesions of multiple sclerosis were devoid of TMEM119 expression [ 45 ].…”

“…Due to the decrease in its expression in an activated microglial status, P2RY12 is usually described as a homeostatic marker [ 53 , 59 ]. However, Zravy et al [ 46 ], detected a return of low numbers of P2RY12-positive cells in the late stages of the injury process in human spinal cord injury.…”

Neuropathological Variability within a Spectrum of NMDAR‐Encephalitis

“…Visualization was performed by using (1) alkaline phosphatase-conjugated secondary antibodies for subsequent development with fast blue BB salt as well as (2) biotinylated secondary antibodies and peroxidase-conjugated streptavidin for subsequent development with aminoethyl carbazole (AEC). 17,18 NMDAR Antibody Testing CSF NMDAR antibodies were assessed using an in-house tissue-based assay as described elsewhere 1 and a commercial cell-based assay (Euroimmun, Lübeck, Germany) according to the manufacturer's protocol. Positivity was defined as a positive neuropil staining pattern in the tissue-based assay and positive labeling of transfected cells.…”