Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice.
During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.
Chiu
Isaac M
IM
Program in Cellular and Molecular Medicine, Immune Disease Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Phatnani
Hemali
H
Kuligowski
Michael
M
Tapia
Juan C
JC
Carrasco
Monica A
MA
Zhang
Ming
M
Maniatis
Tom
T
Carroll
Michael C
MC
D000375:Aging / Q000276:immunology / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D000818:Animals; D003181:Complement C4 / Q000276:immunology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D056724:Immunity, Humoral / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000294:innervation / Q000473:pathology; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D017933:Peripheral Nervous System / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000235:genetics
D003181:Complement C4; D049452:Green Fluorescent Proteins; D013482:Superoxide Dismutase