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Am J Neurodegener Dis 2012;1(1):60-74

Original Article
Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord:
inhibition of inflammation by resolvin D1

Guanghao Liu, Milan Fiala, Mathew T Mizwicki, James Sayre, Larry Magpantay, Avi Siani, Michelle Mahanian, Madhuri
Chattopadhay, Antonio La Cava, Martina Wiedau-Pazos

1Department of Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System,
650 Charles E. Young Dr. South, Los Angeles, CA 90095-1735, USA; 2Department of Biostatistics, University of
California School of Public Health, Los Angeles, CA, USA; 3Obstetrics and Gynecology, David Geffen School of
Medicine, University of California, Los Angeles, CA, USA; 4Department of Chemistry and Biochemistry, UCLA, Los
Angeles, CA 90095, USA; 5Department of Medicine, David Geffen School of Medicine at UCLA, USA; 6Department of
Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Received March 8, 2012; accepted March 13, 2012; Epub March 15, 2012; published May 30, 2012

Abstract: Although the cause of neuronal degeneration in amyotrophic lateral sclerosis (ALS) remains hypothetical,
there is evidence of spinal cord infiltration by macrophages and T cells. In post-mortem ALS spinal cords, 19.8 + 4.8 %
motor neurons, including caspase–negative and caspase-positive neurons, were ingested by IL-6- and TNF-α-positive
macrophages. In ALS macrophages, in vitro aggregated superoxide dismutase-1 (SOD-1) stimulated in ALS
macrophages expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, through activation of
cyclooxygenase-2 (COX-2) and caspase-1. The lipid mediator resolvin D1 (RvD1) inhibited IL-6 and TNF-α production
in ALS macrophages with 1,100 times greater potency than its parent molecule docosahexaenoic acid.  ALS peripheral
blood mononuclear cells (PBMCs) showed increased transcription of inflammatory cytokines and chemokines at
baseline and after stimulation by aggregated wild-type SOD-1, and these cytokines were down regulated by RvD1.
Thus the neurons are impacted by macrophages expressing inflammatory cytokines. RvD1 strongly inhibits in
macrophages and PBMCs cytokine transcription but does not inhibit their production in PBMCs. Resolvins offer a new
approach to ALS inflammation suppressing. (AJND1103001)

Keywords: Amyotrophic lateral sclerosis (ALS), superoxide dismutase 1 (SOD1), interleukin-17A (IL-17A), interleukin-6
(IL-6), tumor necrosis factor-a, docosahexaenoic acid (DHA), resolvin D1 (RvD1), inflammation

Address all correspondence to:
Milan Fiala, MD
UCLA 23-338 CHS, 650 Charles E. Young Dr. S.
Los Angeles, CA 90095-1735, USA.
Phone: 310 206-6392; FAX 310 246-1321
E-mail: fiala@mednet.ucla.edu