Role of Complement in a Model of Paclitaxel-Induced Peripheral Neuropathy
Jijun Xua,b,*, Lingjun Zhanga, Mian Xiea, Yan Lia, Ping Huanga, Thomas L Saundersc, David A Foxd, Richard Rosenquistb, and Feng Lina,*
a Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
b Department of Pain Management, Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
c Transgenic Animal Model Core Facility, University of Michigan, Ann Arbor, MI 48109, USA
d Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI 48109, USA
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating painful side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the currently available therapy used to treat this neuropathic pain syndrome is inadequate, leaving many patients to suffer from a disabling quality of life. Complement, an important component of the innate immune system, has been associated with neuro-inflammation, which is emerging as an important trigger for neuropathic pain; however, the role of complement in CIPN remains unclear.
We first developed a complement C3 knockout (KO) rat, then induced CIPN in both C3 KO rats and their wild-type (WT) littermates by intraperitoneal administration of paclitaxel, a chemotherapy agent associated with CIPN. We examined mechanical allodynia using von Frey filaments. Complement activation was assessed by western blotting. Loss of intradermal nerve fibers was investigated in the hindpaw skin by immunostaining. Complement antagonists were administered intrathecally to evaluate their effects on mechanical allodynia.
We confirmed the absence of C3 in the resultant C3 KO rats by sequencing, western blot, and complement functional assays and found that 1) intraperitoneal administration of paclitaxel activated complement in WT rats; 2) mechanical allodynia induced by paclitaxel was less severe in C3 KO rats than in WT rats; and 3) paclitaxel-induced loss of intradermal nerve fibers was reduced in C3 KO rats. Furthermore, intrathecal administration of C3a or C5a receptor antagonists alleviated mechanical allodynia induced by paclitaxel in WT rats.
These results demonstrated a previously unknown, but pivotal, role of complement in CIPN, suggesting that complement receptors may be new targets for the development of novel therapeutics for the management of this painful disease.
Keywords: Chemotherapy-induced neuropathy – Complement – Inflammation - Pain