Abstract
The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.
Highlights
Complement PathwaysThe complement is a major component of the innate immune system and acts as a bridge between innate and acquired immunity
Introduction published maps and institutional affilThe complement system is a crucial element of the innate immune response that works in concert with antibodies and phagocytic cells to clear pathogens [1]
Guillain-Barré syndrome (GBS) is a clinically heterogeneous spectrum of rare post-infectious neuropathies that usually occur in otherwise healthy patients and encompasses acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), Miller–Fisher syndrome (MFS) and some other regional variants [46,47,48]
Summary
The complement is a major component of the innate immune system and acts as a bridge between innate and acquired immunity. The activated LP complex has an oligomer structure similar to the pentamolecular C1 complex [15] and is triggered by serine proteases associated with mannose-binding lectins (MBLs) and with ficolins, another family of lectins, which are able to recognize pathogens [16] Upon activation by these signals, the enzymes of the complex mannan-binding lectin serine protease (MASP) 1 and 2 mediate the formation of the C3 convertase C4bC2a, which activates the same downstream pathways as occurs in CP [17]. T-arrow indicates inhibition of pathway at point of intersection As it is a very complex system, various mechanisms can interfere with the complement cascade leading to over-activation and consequent neuronal damage and disease [20]. The following paragraphs describe the more recent major findings in the field of PNS and discuss possible implications of the complement system in the pathogenesis of different neuropathic disorders
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
