Abstract
BackgroundIncreased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS.MethodsMice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed.ResultsCompared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions.ConclusionsThe APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.
Highlights
Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear
The acute phase response (APR) occurs via a cascade of local vascular and systemic effects, facilitated by inflammatory mediators including chemokines, cytokines, pentraxins and serum amyloid proteins, which are largely produced by the liver and are often described as acute phase proteins (APP)
Whilst the production of chemokines and APPs in the periphery was highest at day 10 when the animals were
Summary
Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. We have recently shown that astrocyte-shed extracellular vesicles regulate this peripheral APR to inflammatory brain lesions following acute CNS injuries [5] and that augmentation of the peripheral response can exacerbate acute CNS lesions [6] This appears to be a direct consequence of enhanced mobilisation of leukocytes into the blood by the chemokines released by the liver [7]. The expression of hepatic CXCL1 in the ABH CR-EAE animals occurred well before the development of overt clinical signs and suggests that activation of the APR might precipitate clinical relapses experienced by MS patients [9] In another acute EAE model, hepatic CCL2 and CXCL10 expression have been reported to precede the development of fulminant EAE disease, but it was unclear in this study whether this systemic inflammatory response was a ‘primary determinant or a secondary reflection’ of the occurrence of EAE in the affected animals [14]
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