The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff, Trent M.; Costantini, Kerina J.; Crane, James W.; Atkin, Julie D.; Monk, Peter N.; Taylor, Stephen M.; Noakes, Peter G.

doi:10.4049/jimmunol.181.12.8727

Cited by 140 publications

(199 citation statements)

References 41 publications

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“…Complement factors are mostly synthesized in the liver, but in mSOD1 transgenic animal models, complement factor C1q transcription was noted to be upregulated in motor neurons [102]. However, the role of the complement pathway still remains controversial [103][104][105][106]. The role of peripheral monocytes in ALS is also controversial.…”

Section: Additional Peripheral Immune Contributionsmentioning

confidence: 99%

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

et al. 2015

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Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

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Section: Additional Peripheral Immune Contributionsmentioning

confidence: 99%

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

et al. 2015

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“…At presymptomatic time points (i.e., weeks 9-12), focal activation occurs for PNS macrophages and spinal cord microglia. Following clinical onset (i.e., weeks [12][13][14][15][16][17][18][19], activation of innate immunity becomes widespread in both tissues as indicated by FACS and histological analysis.…”

Section: Macrophage Activation Occurs Throughout the Peripheral Nervousmentioning

confidence: 99%

“…Humoral system components, including circulating antibodies and complement, are known to deposit in the ALS spinal cord, and may play significant roles in damaging motor neurons (6,17). In acute PNS injury, complement mediates the opsonization of myelin debris and recruitment of myeloid cells (18,19).…”

Section: Macrophage Activation Occurs Throughout the Peripheral Nervousmentioning

confidence: 99%

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

Chiu

Phatnani

Kuligowski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

175

176

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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

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“…18 The same phenomenon was also documented in amyotrophic lateral sclerosis. 19 Besides, it has been demonstrated that PMX53 protected IRI in the heart, liver, kidneys, limb and small intestine. 20 However, the role of PMX53 in SIRI remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term

et al. 2015

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Study design: Experimental study. Objectives: To investigate the effect of pre-treatment with PMX53, a C5aR antagonist, on spinal cord ischemia-reperfusion injury (IRI) in rat. Setting: Department of Neurosurgery, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi Province, China. Methods: IRI was induced in the lumbar spinal cord by applying a mini aneurysm clamp to the abdominal aorta for 60 min in adult Sprague-Dawley rats. PMX53 (1 mg kg − 1 ) was administered through femoral vein injection 30 min before ischemia on the rats in the PMX53 group (n = 18). The saline group (n = 18) was given saline at the same volume through femoral vein injection. The neurologic outcome of the posterior limbs was assessed by the Basso-Beattie-Bresnahan (BBB) score at 1, 6, 12, 24 and 48 h after reperfusion. Histologic changes of the spinal cord were detected with hematoxylin-eosin (H-E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect myeloperoxidase (MPO) activity in the spinal cord. Immunohistochemistry was used to investigate the quantity of activated astrocytes and microglia. Results: After pre-treatment with PMX53, neurologic function improved gradually after 6, 12, 24 and 48 h reperfusion. The BBB score of the PMX53 group increased significantly (Po0.05) compared with the saline group. H-E staining showed that pathologic damage in the PMX53 group was reduced. Moreover, administration of PMX53 significantly inhibited neutrophil infiltration in the spinal cord. Levels of MPO activity in the spinal cord were remarkably lower in the PMX53 group (Po0.05). There were also more activated microglia and astrocytes in the spinal cord of the PMX53 group than in the saline group (Po0.05). INTRODUCTIONSpinal cord ischemia-reperfusion injury (SIRI) mainly occurs after operations on the descending thoracic or thoracoabdominal aorta, such as thoracoabdominal aneurysm. 1 SIRI causes various complications, including paraparesis and paraplegia. 2 These complications have been attributed to temporary or permanent ischemia of the spinal cord caused by interruption of the blood supply during aortic cross-clamping. The incidence of paraplegia has been correlated with dissection, rupture and prolonged clamp times. 3 Systemic hypothermia, spinal fluid drainage and preconditioning ischemia were considered to prevent paraplegia, 4 but the effect was limited. Recent studies indicated that pathophysiological mechanisms underlying SIRI are complicated, including the release of inflammatory factors, 5 calcium overload, 6 oxidative stress, 7 excitotoxicity 8 and neuronal apoptosis. 9,10 In addition, there are more mechanisms that remain unclear. It has been found that the inflammatory cascade is activated due to SIRI, including neutrophil and neuroglia mobilization and infiltration, as well as elevated levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6. 11 The complement system, a major component of the innate immune system, is

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The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Cited by 140 publications

References 41 publications

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

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

PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term

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