Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Wang, Haitao A., Lee, John D., Lee, Kah Meng, Woodruff, Trent M. and Noakes, Peter G. (2017) Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Skeletal Muscle, 7 1: . doi:10.1186/s13395-017-0128-8


Author Wang, Haitao A.
Lee, John D.
Lee, Kah Meng
Woodruff, Trent M.
Noakes, Peter G.
Title Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Formatted title
Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Journal name Skeletal Muscle   Check publisher's open access policy
ISSN 2044-5040
Publication date 2017-06-01
Sub-type Article (original research)
DOI 10.1186/s13395-017-0128-8
Open Access Status DOI
Volume 7
Issue 1
Total pages 11
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background: The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Terminal complement activation leads to generation of C5a, which through its receptor, C5aR1, drives immune cell recruitment and activation. Importantly, genetic or pharmacological blockage of C5aR1 improves motor performance and reduces disease pathology in hSOD1G93A rodent models of ALS. In this study, we aimed to explore the potential mechanisms of C5aR1-mediated pathology in hSOD1G93A mice by examining their skeletal muscles.

Results: We found elevated levels of C1qB, C4, fB, C3, C5a, and C5aR1 in tibialis anterior muscles of hSOD1G93A mice, which increased with disease progression. Macrophage cell numbers also progressively increased in hSOD1G93A muscles in line with disease progression. Immuno-localisation demonstrated that C5aR1 was expressed predominantly on macrophages within hSOD1G93A skeletal muscles. Notably, hSOD1G93A × C5aR1-/- mice showed markedly decreased numbers of infiltrating macrophages, along with reduced neuromuscular denervation and improved grip strength in hind limb skeletal muscles, when compared to hSOD1G93A mice.

Conclusion: These results indicate that terminal complement activation and C5a production occur in skeletal muscle tissue of hSOD1G93A mice, and that C5a-C5aR1 signalling contributes to the recruitment of macrophages that may accelerate muscle denervation in these ALS mice.
Keyword C5
C5aR1
Complement
Inflammation
Macrophages
Skeletal muscle
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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