Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy

• Published in: The Journal of immunology (1950) Vol. 200; no. 12; pp. 4094 - 4101
• Main Authors: Xu, Jijun, Zhang, Lingjun, Xie, Mian, Li, Yan, Huang, Ping, Saunders, Thomas L, Fox, David A, Rosenquist, Richard, Lin, Feng
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.06.2018
• Subjects: Animals; Cancer; Chemotherapy; Complement activation; Complement component C3; Complement System Proteins - immunology; Complement System Proteins - pharmacology; Disease Models, Animal; Drug development; Hyperalgesia - chemically induced; Hyperalgesia - immunology; Immune system; Immunity, Innate - drug effects; Immunity, Innate - immunology; Inflammation; Innate immunity; Nerve Fibers - drug effects; Nerve Fibers - immunology; Neuralgia - chemically induced; Neuralgia - immunology; Paclitaxel; Pain perception; Pathogenesis; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - immunology; Peripheral neuropathy; Quality of Life; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rodents
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1701716

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.