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The Journal of Neuroscience, February 11, 2004, 24(6):1340-1349; doi:10.1523/JNEUROSCI.4786-03.2004

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

Minh Dang Nguyen,¹ Thierry D'Aigle,² Geneviève Gowing,^1,2 Jean-Pierre Julien,^1,2 and Serge Rivest²

¹McGill University Health Center, Centre for Research in Neurosciences, McGill University, The Montreal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada, and ²Laboratory of Molecular Endocrinology, Laval University Medical Center Research Center and Department of Anatomy and Physiology, Laval University, Sainte-Foy, Québec G1V 4G2, Canada

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, SOD1^G37R 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.

Key words: innate immunity; neurodegeneration; lipopolysaccharide; microglia; amyotrophic lateral sclerosis; superoxide dismutase 1; proinflammatory cytokines; transgenic mice

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Received July 23, 2003; revised November 28, 2003; accepted December 3, 2003.

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