Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain

TLDR

The potential link between microbial infection and reactivation of multiple sclerosis lesions remains unresolved, largely due to a lack of suitable animal models and imaging techniques. Here, we empirically examined this question using immunohistochemistry and magnetic resonance imaging before and after inducing a systemic inflammatory response in two distinct MS models. We assessed lesion activity by measuring regional cerebral blood volume, magnetization transfer ratio, tissue water diffusion, leukocyte recruitment, and endothelial selectin expression with MRI and immunohistochemical techniques. Systemic endotoxin injection in both pattern‑II and pattern‑I MS models increased regional cerebral blood volume, reduced magnetization transfer ratio, elevated tissue water diffusion, recruited leukocytes, and induced E‑ and P‑selectin expression, indicating that infection can reactivate quiescent lesions and alter blood–brain barrier integrity, with implications for MS management.

Abstract

The potential association between microbial infection and reactivation of a multiple sclerosis (MS) lesion is an important issue that remains unresolved, primarily because of the absence of suitable animal models and imaging techniques. Here, we have evaluated this question in an empirical manner using immunohistochemistry and magnetic resonance imaging (MRI), before and after the induction of a systemic inflammatory response in two distinct models of MS. In a pattern-II-type focal myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis model, systemic endotoxin injection caused an increase in regional cerebral blood volume (rCBV) around the lesion site after 6 h, together with a reduction in the magnetization transfer ratio of the lesioned corpus callosum. These changes were followed by an increase in the diffusion of tissue water within the lesion 24 h after endotoxin challenge and new leukocyte recruitment as revealed both immunohistochemically and by MRI tracking of ultrasmall superparamagnetic iron oxide-labeled macrophages. Importantly, we detected in vivo expression of E- and P-selectin in quiescent lesions by MRI-detectable glyconanoparticles conjugated to sialyl Lewis X . This finding may explain, at least in part, the ability of quiescent MS lesions to rapidly reinitiate the cell recruitment processes. In a pattern-I-type delayed-type hypersensitivity response model, a similar effect of endotoxin challenge on rCBV was observed, together with delayed breakdown of the blood–brain barrier, showing that systemic infection can alter the pathogenesis of MS-like lesions regardless of lesion etiology. These findings will have important implications for the management and monitoring of individuals with MS.