Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS

Wang, Haitao (2015). Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS PhD Thesis, School of Biomedical Sciences, The University of Queensland. doi:10.14264/uql.2016.3

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Author Wang, Haitao
Thesis Title Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS
Formatted title
Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS
School, Centre or Institute School of Biomedical Sciences
Institution The University of Queensland
DOI 10.14264/uql.2016.3
Publication date 2015-12-18
Thesis type PhD Thesis
Supervisor Peter Noakes
Trent Woodruff
Total pages 119
Language eng
Subjects 1109 Neurosciences
1107 Immunology
Formatted abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease. It is characterised by progressive loss of motor neurons and muscle atrophy. Recently, mounting evidence has suggested that complement, part of the innate immune system, is involved in the pathogenesis of ALS in both human patients and in animal models. Activation of complement in the central nervous system (CNS) has been well defined and has been proved to be critical to the death of motor neurons. However, less is known about the roles of complement in the skeletal muscle during the ALS disease progression.

The initial aim of this study was to examine the complement activation in skeletal muscle of hSOD1G93A mice, a well-characterised ALS animal model. Expressions of major complement factors (C1qB, C3, factor B, C4, C5, C5aR1, and C3aR) and regulators (CD55, CD59) were determined, and shown to be significantly elevated in the skeletal muscle of hSOD1G93A when compared to wide-type (WT) mice as disease progressed, suggesting that complement activation in the skeletal muscle of hSOD1G93A mice is achieved through classical and possibly other complement cascades. In addition, expression levels of C5aR1 and C3aR, receptors for complement peptides C5a and C3a respectively, were also increased. Immunolocalisation studies shows that C5aR1 and C3aR are expressed on invading immune cells, CD11b+ macrophage and CD4+ helper T cells, in skeletal muscle of hSOD1G93A mice.

The second aim of this study was to investigate the physiological roles of complement signalling in regulating immune cell migration in skeletal muscle of hSOD1G93A mice. Massive invasions of macrophage and helper T cells were observed in tibialis anterior muscles of hSOD1G93A mice when compared to age-matched wild-type mice. These infiltrations were remarkably attenuated in hSOD1G93A mice lacking either C5aR1 or C3aR. By contrast, there was significantly less immune cell invasion into soleus muscles of hSOD1G93A mice, but like for the tibialis anterior muscle, this invasion is significantly greater when compared to soleus muscles from age-matched wild-type mice, and attenuated in soleus muscle from hSOD1G93A mice lacking either C5aR1 or C3aR. The soleus muscle, predominantly a slow-twitch muscle, is less vulnerable to denervation in hSOD1G93A mice. Taken together, these results indicate that C5a-C5aR1 and C3a-C3aR signalling regulates the migration of immune cells into the skeletal muscle during ALS disease progression, and the extent of immune cell influx is related to physiological function of skeletal muscle.

In summary, I have shown activation of the complement system in the skeletal muscle of hSOD1G93A ALS mouse model, suggesting a role of complement C5a-C5aR1 and C3a-C3aR signalling in recruiting immune cells into skeletal muscle during disease progression. As skeletal muscle is the prime target for ALS, these findings may promote skeletal muscle as a therapeutic target for effects of complement factors in ALS treatment.
Keyword Complement
SOD
C5aR1
C3aR
Macrophage
T cell
Skeletal muscle
Amyotrophic lateral sclerosis (ALS)
Motor neuron disease

Document type: Thesis
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Created: Fri, 04 Dec 2015, 11:56:40 EST by Mr Hai Tao Wang on behalf of University of Queensland Graduate School