Pharmacological inhibition of complement C5a‐C5a<sub>1</sub> receptor signalling ameliorates disease pathology in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis

Lee, John D.; Kumar, Vinod; Fung, J.; Ruitenberg, Marc J.; Noakes, Peter G.; Woodruff, Trent M.

doi:10.1111/bph.13730

Cited by 78 publications

(82 citation statements)

References 33 publications

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“…The present study clearly demonstrated a marked reduction in overall inflammatory markers in the spinal cord including decreases in pro-inflammatory cytokines TNF α and IL-1β, the RAGE ligand and danger-associated molecular pattern molecule HMGB1, innate immune receptors TLR4 and C5aR1, inflammasome component NLRP3, and an oxidative stress marker. This is consistent with many prior studies demonstrating these components play pathogenic roles in ALS disease progression [35,36,40-43,20,19,37,44]. Interestingly, genetic deletion of RAGE also resulted in a down-regulation of the complement components C1qb and C3.…”

Section: Discussionsupporting

confidence: 92%

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Lee

McDonald

Fung

et al. 2020

Preprint

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1Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron 2 degenerative disease that is without effective treatment. The receptor for advanced glycation 3 end products (RAGE) is a major component of the innate immune system that has been 4 implicated in ALS pathogenesis. However, the contribution of RAGE signaling to the 5 neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study 6 therefore generated SOD1 G93A mice lacking RAGE, and compared them to SOD1 G93A 7 transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle 8 strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior 9 muscle. We found that complete absence of RAGE signaling exerted a protective effect on 10 SOD1 G93A pathology, slowing disease progression and significantly extending survival by ~3 11 weeks, and improving motor function (rotarod and grip strength). This was associated with 12 reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), 13 and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis 14 anterior muscle. We also documented that RAGE mRNA expression was significantly 15 increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, 16 supporting a widespread involvement for RAGE in ALS pathology. In summary, our results 17 indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration 18 in ALS, and highlights RAGE as a potential immune therapeutic target for ALS. 19 20 21 22 23 24

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Section: Discussionsupporting

confidence: 92%

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Lee

McDonald

Fung

et al. 2020

Preprint

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“…A micro-array study further confirmed evidence for mild neutrophilia in ALS patients (55). In the SOD1 G93A transgenic mouse ALS model, circulating neutrophils are increased (73), and neutrophils and mast cells are present along peripheral motor axons, with masitinib treatment leading to reduction of axonal damage (56). This suggests these cells are harmful and contribute to disease progression.…”

Section: Abnormalities Of Peripheral Blood Cells Total Leukocyte Counmentioning

confidence: 79%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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“…K E Y W O R D S glia, IL-1β, innate immunity, motor neuron disease 1 | INTRODUCTION Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive neurodegenerative disease caused by the deterioration of motor neurons within motor cortex, brain stem, and spinal cord (Lee et al, 2017;Paez-Colasante, Figueroa-Romero, Sakowski, Goutman, & Feldman, 2015;Sibilla & Bertolotti, 2017). Current therapies for ALS are inadequate.…”

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confidence: 99%

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Deora

Lee

Albornoz

et al. 2019

Glia

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Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1G93A was unable to induce IL‐1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1‐induced microglial IL‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43Q331K ALS mouse model, and TDP‐43 wild‐type and mutant proteins could also activate microglial inflammasomes in a NLRP3‐dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A‐mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.

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Pharmacological inhibition of complement C5a‐C5a₁ receptor signalling ameliorates disease pathology in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract: These results confirm that C5a receptors play a pathogenic role in hSOD1 mice, further validating the C5a-C5a receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.

Cited by 78 publications

References 33 publications

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

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Pharmacological inhibition of complement C5a‐C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract: These results confirm that C5a receptors play a pathogenic role in hSOD1 mice, further validating the C5a-C5a receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.

Cited by 78 publications

References 33 publications

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

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Product

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Pharmacological inhibition of complement C5a‐C5a₁ receptor signalling ameliorates disease pathology in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis