Inflammatory Macrophages in ALS Spinal Cord

In my many conversation with Neuro-disease researchers, I often learn of discoveries that beg to be shared. I have been collaborating with Dr. Milan Fiala to explore how our hN2 Primary Human Neurons could be best used to study the role of inflammatory cytokines in amyotrophic lateral sclerosis (ALS). This would build on the excellent research he and his team are conducting at UCLA.

He shared with me that these inflammatory cytokines could be the bad actors in ALS. Specifically, in vitro, superoxide dismutase-1 (SOD-1) stimulates expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, through activation of cyclooxygenase-2 (COX-2) and caspase-1. Further, they have discovered 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 ALS macrophages and PBMCs cytokine transcription and production. Resolvins offer a new approach to suppression of inflammatory activation in ALS. To learn more see: Guanghao Liu, Milan Fiala, Mathew T. Mizwicki, James Sayre, Larry Magpantay, Avi Siani, Michelle Mahanian, Madhuri Chattopadhyay, Antonio La Cava, and Martina Wiedau-Pazos. Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord: inhibition of inflammation by resolvin D1.
Am J Neurodegener Dis. 2012;1(1):60-74.

Images: Co localization of TNF-a- and IL-6- expressing macrophages with caspase-3-and the chemokine RANTES (CCL5) – stained neurons in ALS and control spinal cords. Frozen sections of ALS and control lumbar spinal cord were stained with anti-NeuN (red), anti-CD68 (green), anti-caspase-3 (magenta) or anti-RANTES (magenta), and DAPI (blue) (Immunofluorescence microscopy (20X)). The experiment was repeated with 2 other ALS spinal cords and 2 other control spinal cords and yielded comparable results.
Photomicrographs are shown in 2 patients (A, B, C, D) and 2 controls (E, F). (A) Co
localization (yellow) of TNF-a-positive (magenta) and (CD68-positive, green) macrophages with NeuN–positive (red) neurons; (B) Co localization (yellow) of IL-6-positive (magenta) and CD68-positive (green) macrophages with NeuN–positive (red) neurons; (C) Co localization of macrophages (CD68-positive, green) with apoptotic, caspase-3-positive (magenta) and non-apoptotic (caspase-3-negative (red)) neurons. Eight neurons are impacted by macrophages; 3 neurons are caspase-3-positive (arrows) and 5 neurons are caspase-3- negative (asterisk); (D) Co localization of macrophages (yellow) with RANTES-positive (magenta) and CD 68-positive (green) macrophages with NeuN-positive (red) neurons. (E&F) No macrophages (green) are detected in 3 control spinal cords. (G&H) The table shows that in three ALS spinal cords 19.2 +/−4.8% NeuN-positive (red) neurons co localize with TNF-a -positive (magenta) macrophages (green) and 18.5 +/− 4.9 % NeuN-positive (red) neurons co localize with IL-6-positive (magenta) macrophages (green), whereas in control spinal cords 0% neurons (red) co localize with macrophages (green).

I will keep you posted on progress.

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