The complement factor C5a receptor is upregulated in NFL−/− mouse motor neurons

Humayun, Saima; Gohar, M. A.; Volkening, Kathryn; Moisse, Katie; Leystra-Lantz, Cheryl; Mepham, Jennifer; McLean, Jesse R.; Strong, Michael J.

doi:10.1016/j.jneuroim.2009.01.028

Cited by 37 publications

(51 citation statements)

References 54 publications

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“…The up-regulation of the classical pathway complement components C1q and C4, as well as of the central factor C3, has been shown in human SOD1 transgenic rodent models of ALS (Lee et al, 2012). Other studies have also shown the up-regulation of the major pro-inflammatory C5a receptor, CD88, during disease progression (Humayun et al, 2009, Woodruff et al, 2008a. In addition, our group has shown that chronic administration of a specific CD88 antagonist in hSOD1 G93A transgenic rats delayed the onset of motor symptoms and increased survival compared to untreated animals (Woodruff et al, 2008a).…”

Section: Introductionsupporting

confidence: 53%

“…This study showed that there was a 4 and 3 fold increase in CD88 mRNA expression level at 2 and 3 months respectively, a time which is early in the disease process (Humayun et al, 2009). There was also an increased immunoreactivity of CD88 in motor neurons of NFL deficient mice when compared to WT mice at 3, 4 and 5 months.…”

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 53%

“…In particular, CD88 activation seemed to be the driver of CNS pathology in numerous neurodegenerative diseases including AD, HD and ALS (Farkas et al, 2003, Fonseca et al, 2009, Fonseca et al, 2013, Singhrao et al, 1999, Woodruff et al, 2006, Woodruff et al, 2008a, Humayun et al, 2009). This was demonstrated by increased CD88 expression in human tissue and protection in animal models using a specific CD88 antagonist PMX205 (Fonseca et al, 2009, Woodruff et al, 2006, Woodruff et al, 2008a).…”

Section: Role Of C5a In Cns Diseasesmentioning

confidence: 99%

“…To further validate the involvement of downstream components of the complement cascade in the disease progression of ALS, up-regulation of C5a receptor CD88 mRNA and protein was observed in mice deficient in the low molecular weight neurofilament (NFL) subunit protein, a mouse model of motor neuron degeneration in which neurofilament aggregates in a similar fashion to that in ALS patients (Humayun et al, 2009). This study showed that there was a 4 and 3 fold increase in CD88 mRNA expression level at 2 and 3 months respectively, a time which is early in the disease process (Humayun et al, 2009).…”

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 99%

“…Additionally, given the importance of C5a in disease pathology in ALS models (Humayun et al, 2009, Woodruff et al, 2008a we also examined mRNA, protein levels, and the cellular localisation of C5, C5a and its cognate receptor, CD88 during disease progression. Our findings demonstrate a global dysregulation of complement, as disease progressed in these murine models of human ALS.…”

Section: Introductionmentioning

confidence: 99%

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The role of complement system in amyotrophic lateral sclerosis

Lee¹

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There is increasing evidence that neuro-inflammation drives disease progression in many neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS). Components of the innate immune complement system have been implicated in the pathogenesis of ALS. Within the complement signalling cascade C3a and C5a are regarded as potent inflammatory and immunomodulatory peptides with various biological functions. In the CNS their functions include chemotaxis and proliferation of microglia and astrocytes; generation of superoxide radicals; and induction of pro-inflammatory cytokine synthesis -all thought to be achieved via their main signalling receptors C3aR and CD88. Some of these functions have been observed in neurodegenerative disease, suggesting that these complement factors may play a role in ALS pathogenesis. However a comprehensive examination of complement expression and function of C3aR and CD88 in this disease has not been performed.The initial aim of this thesis was to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5, CD88 and C3aR) and regulators (CD55 and CD59a) in the lumbar spinal cord of the transgenic hSOD1 G93A mouse model of ALS. This was conducted during distinct disease stages, which were defined in this thesis. We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1 G93A mice. CD88 and C3aR was also increased during disease progression, with immunolocalization demonstrating expression on motor neurons and increasing expression of CD88 on microglia and increasing expression of C3aR on astrocytes surrounding the regions of motor neuron death.Our previous studies have demonstrated that hSOD1 G93A rats treated with the selective CD88 antagonist PMX205 had reduced gliosis and improvements in behavioural deficits, consistent with reduced neuropathology; suggesting CD88 has a pathogenic function in ALS. However, the contribution of C3aR to disease progression in ALS is still unknown. This thesis therefore next aimed to confirm the function of CD88, and determine the function of C3aR, in the disease progression of ALS in hSOD1 G93A mice. The function of CD88 signalling was investigated using two different approaches (pharmacological and genetic). Inhibition of CD88 using PMX205 (pharmacological approach) or hSOD1 G93A mice lacking CD88 (genetic approach) showed similarly extended survival when compared to vehicle and hSOD1 G93A mice. There was also a reduction in microglia, monocytes and cytokines (TNFα and IL-1β) transcripts in the spinal cord at the end-stage of disease. Taken together these results indicate that inhibition of CD88 significantly attenuates III disease progression potentially by reducing microglia/monocyte activation...

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Section: Introductionsupporting

confidence: 53%

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 53%

Section: Role Of C5a In Cns Diseasesmentioning

confidence: 99%

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of complement system in amyotrophic lateral sclerosis

Lee¹

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Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

Kopper

Gensel

2017

J of Neuroscience Research

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Spinal cord injury (SCI) triggers chronic intraspinal inflammation consisting of activated resident and infiltrating immune cells (especially microglia/macrophages). The environmental factors contributing to this protracted inflammation are not well understood, however, myelin lipid debris is a hallmark of SCI. Myelin is also a potent macrophage stimuli and target of complement-mediated clearance and inflammation. The downstream effects of these neuro-immune interactions have the potential to contribute to ongoing pathology or facilitate repair. This depends in large part on whether myelin drives pathological or reparative macrophage activation states, commonly referred to as M1 (pro-inflammatory) or M2 (alternatively) macrophages respectively. Here we review the processes by which myelin debris may be cleared through macrophage surface receptors and the complement system, how this differentially influences macrophage and microglial activation states, and how the cellular functions of these myelin macrophages and complement proteins contribute to chronic inflammation and secondary injury after SCI.

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The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System

et al. 2009

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The complement system is a pivotal component of the innate immune system which protects the host from infection and injury. Complement proteins can be induced in all cell types within the central nervous system (CNS), where the pathway seems to play similar roles in host defense. Complement activation produces the C5 cleavage fragment C5a, a potent inflammatory mediator, which recruits and activates immune cells. The primary cellular receptor for C5a, the C5a receptor (CD88), has been reported to be on all CNS cells, including neurons and glia, suggesting a functional role for C5a in the CNS. A second receptor for C5a, the C5a-like receptor 2 (C5L2), is also expressed on these cells; however, little is currently known about its potential role in the CNS. The potent immune and inflammatory actions of complement activation are necessary for host defense. However, if over-activated, or left unchecked it promotes tissue injury and contributes to brain disease pathology. Thus, complement activation, and subsequent C5a generation, is thought to play a significant role in the progression of CNS disease. Paradoxically, complement may also exert a neuroprotective role in these diseases by aiding in the elimination of aggregated and toxic proteins and debris which are a principal hallmark of many of these diseases. This review will discuss the expression and known roles for complement in the CNS, with a particular focus on the pro-inflammatory end-product, C5a. The possible overarching role for C5a in diseases of the CNS is reviewed, and the therapeutic potential of blocking C5a/CD88 interaction is evaluated.

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The complement factor C5a receptor is upregulated in NFL−/− mouse motor neurons

Cited by 37 publications

References 54 publications

The role of complement system in amyotrophic lateral sclerosis

The role of complement system in amyotrophic lateral sclerosis

Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System

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