Exacerbation of Motor Neuron Disease by Chronic Stimulation of Innate Immunity in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Innate immunity is a specific and organized immunological program engaged by peripheral organs and the CNS to maintain homeostasis after stress and injury. In neurodegenerative disorders, its putative deregulation, featured by inflammation and activation of glial cells resulting from inherited mutations or viral/bacterial infections, likely contributes to neuronal death. However, it remains unclear to what extent environmental factors and innate immunity cooperate to modulate the interactions between the neuronal and non-neuronal elements in the perturbed CNS. In the present study, we addressed the effects of acute and chronic administration of lipopolysaccharide (LPS), a Gram-negative bacterial wall component, in a genetic model of neurodegeneration. Transgenic mice expressing a mutant form of the superoxide dismutase 1 (SOD1 G37R ) linked to familial amyotrophic lateral sclerosis were challenged intraperitoneally with a single nontoxic or repeated injections of LPS (1 mg/kg). At different ages, SOD1G37R mice responded normally to acute endotoxemia. Remarkably, only a chronic challenge with LPS in presymptomatic 6-month-old SOD1 G37R mice exacerbated disease progression by 3 weeks and motor axon degeneration. Closely associated with the severity of disease is the stronger and restricted upregulation of the receptor of innate immunity Toll-like receptor 2 and proinflammatory cytokines in degenerating regions of the ventral spinal cord and efferent fiber tracts of the brain from the LPS-treated SOD1 G37R mice. This robust immune response was not accompanied by the establishment of acquired immunity. Our results provide solid evidence that environmental factors and innate immunity can cooperate to influence the course of disease of an inherited neuropathology.

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

“…But this inflammatory response alters the number, morphology, and sensitivity of microglia such that the brain becomes primed and more vulnerable to subsequent inflammatory insults (Sly et al, 2001;Lee et al, 2002;Nguyen et al, 2004). These insults may then impact on the rate of neurodegeneration.…”

“…Repeated stimulations with LPS have not been performed in these studies, because these animals are known to become tolerant to LPS after repeated challenge (Greer and Rietschel, 1978;Ziegler-Heitbrock, 1995). However, it has been shown in the superoxide dismutase-1 G37R model of amyotrophic lateral sclerosis that a relatively severe chronic stimulation with LPS exacerbates neuronal death and motor neuron axon degeneration (Nguyen et al, 2004). That a less severe inflammatory challenge is also sufficient to induce acute neuronal death may have important consequences for patients with chronic neurodegenerative disease subsequently exposed to common low-grade peripheral infections.…”

Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

“…In some conditions, a pre-existing inflammation can induce brain neurodegeneration. This is the case for the acute peripheral and/or central injection of LPS (Nguyen et al, 2004;Cunningham et al, 2005;McColl et al, 2007;Qin et al, 2007;Spencer et al, 2007). However, it appears that the LPS dose used in these models may be a determinant in the observed degeneration.…”

Expression of Fractalkine Receptor CX3CR1 on Cochlear Macrophages Influences Survival of Hair Cells Following Ototoxic Injury

“…We hypothesize that the high potassium environment of the endolymph may be incompatible with survival of peripheral blood mononuclear cells and that interactions between mononuclear phagocytes and hair cells are brief and might involve extension of processes without migration of the cell body. While direct physical interaction between cochlear macrophages and hair cells appeared rare, there are various scenarios in the central nervous system where macrophages and microglia modulate damage in neurodegeneration via numerous mechanisms, some of which involve signaling through CX3CR1 (Cotter et al 2002;Nguyen et al 2004;Cardona et al 2006;Neumann et al 2006;Denes et al 2008).…”