Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

Abstract

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.innate immunity ͉ macrophage ͉ peripheral nervous system ͉ neuroimmunology ͉ amyotrophic lateral sclerosis

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…The major populations increased in ALS and aging were from monocyte and macrophage lineages. These changes are consistent with other studies that have found robust activation of these cells as part of the immune response during ALS disease progression and aging (Butovsky et al, 2012; Chiu et al, 2009; Galbavy et al, 2017; Kullberg, Aldskogius, & Ulfhake, 2001; Zondler et al, 2016). …”

“…In presymptomatic SOD1 G93A mice, immune activation in the peripheral and central nervous system begins focally and becomes widespread after clinical onset (Alexianu, Kozovska, & Appel, 2001; Chiu et al, 2009; Hall, Oostveen, & Gurney, 1998). Macrophage activation in the peripheral nervous system occurs in parallel with microglial activation and T‐cell infiltration in the spinal cord (Chiu et al, 2009).…”

“…Macrophage activation in the peripheral nervous system occurs in parallel with microglial activation and T‐cell infiltration in the spinal cord (Chiu et al, 2009). During the disease process, spinal cord‐derived microglia recruit inflammatory monocytes, and this process correlates with neuronal loss (Butovsky et al, 2012).…”

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

“…The next signs of impairment appear in the mitochondria and in the cellular transport system (Zhang et al, 1997, Warita et al, 1999, Williamson and Cleveland, 1999, Mattiazzi et al, 2002, Kieran et al, 2005, Damiano et al, 2006, De Vos et al, 2007, Bilsland et al, 2008, Nguyen et al, 2009, Bilsland et al, 2010, Li et al, 2010. The immune response is initiated next (Alexianu et al, 2001, Chiu et al, 2008, Gowing et al, 2008, Chiu et al, 2009. After this, denervation of the motor units and loss of maximal force begins (Kennel et al, 1996, Frey et al, 2000, Fischer et al, 2004, Hegedus et al, 2007, Hegedus et al, 2008, but the impairment of normal function in the mouse is subtle and onset of overt symptoms is several weeks off, even in the most severe models.…”

Role of Astrocytes in Neurodegenerative Diseases

“…These changes include reactive astrocytosis that can be seen many months before motor neuron degeneration (G85R) (Bruijn et al, 1997), and loss of glutamate transport and GLT1 protein expression before the onset of clinical disease or overt motor neuron degeneration (Howland et al, 2002). Similarly, increased astrocytes activation and expression of immune/inflammatory markers are hallmark of this pathology (Chiu et al, 2008;Chiu et al, 2009). Is the reduction in GLT1 protein in astrocytes significant?…”