Macrophage inflammatory protein-1α mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1β up-regulation

Abstract

In the present study, we investigated the role of the macrophage inflammatory protein-1alpha (MIP-1alpha) in the pathogenesis of neuropathic pain following partial sciatic nerve ligation (PSL) in mice. MIP-1alpha mRNA and its protein were dramatically up-regulated after PSL, and MIP-1alpha was localized on macrophages and Schwann cells in the injured sciatic nerve (SCN). PSL-induced long-lasting tactile allodynia and thermal hyperalgesia were prevented by the perineural injection of anti-MIP-1alpha (2ng). Intraneural (20ng) and perineural (100ng) injection of recombinant MIP-1alpha elicited tactile allodynia and thermal hyperalgesia in sham-operated limb. MIP-1alpha receptors (CCR1 and CCR5) mRNA and their proteins were also up-regulated in the SCN after PSL, and were localized on macrophages and Schwann cells. PSL-induced tactile allodynia was attenuated by perineural injection (0.2nmol) of siRNA against CCR1 and CCR5. On the other hand, PSL-induced thermal hyperalgesia was prevented by siRNA against CCR5, but not CCR1. Interleukin-1beta (IL-1beta) mRNA and its precursor protein in macrophages and Schwann cells were also up-regulated in the SCN after PSL, and PSL-induced neuropathic pain was prevented by the perineural injection of anti-IL-1beta (2ng). PSL-induced IL-1beta up-regulation was suppressed by anti-MIP-1alpha and siRNA against CCR1 and CCR5. Perineural injection of nicotine (20nmol), a macrophage suppressor, prevented PSL-induced neuropathic pain and suppressed MIP-1alpha and IL-1beta expressions. In conclusion, we propose a novel critical molecule MIP-1alpha derived from macrophages and Schwann cells that appears to play a crucial role in the development of neuropathic pain induced by PSL.

Inflammaging impairs peripheral nerve maintenance and regeneration

“…Elevated CCL11 serum levels are detected in mice and humans of old age, negatively regulating neurogenesis in the CNS (Villeda et al, 2011) and interfering with nervous system functions. We demonstrated that CCL11 directly interferes with Schwann cell myelination in vitro (Figure 6) and in vivo (Figure 7)—suggesting it as an important component of the dysregulated inflammatory nerve microenvironment impairing peripheral nerve remyelination in old age; a notion supported by age‐dependent increases in CCR5 expression (Supporting information Figure S3C), a CCL11 receptor reported to be expressed by Schwann cells and upregulated upon peripheral nerve injury (Kiguchi et al, 2010). Thus, elevated systemic CCL11 levels may be partly responsible for Schwann cell dedifferentiation and injury‐independent repair program activation (Figure 5) in intact old nerves.…”

“…Moreover, similar to its ligand CCL11, CCR5 was upregulated in old age (Supporting information Figure S3C). CCR5 has been found expressed by both Schwann cells and macrophages, with significant upregulation upon peripheral nerve injury (Kiguchi, Maeda, Kobayashi, Fukazawa, & Kishioka, 2010). We hypothesized that CCL11 may be directly involved in regulation of Schwann cell behavior and tested this in a coculture system with DRG neurons and Schwann cells.…”

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

“…CCR1 is up-regulated in sensory neurons [11] and the spinal cord [7,12] after nerve injury and increased CCR1 mRNA has also been measured in rats 24 hr after receiving carrageenan [13], supporting its involvement in nociceptive processing. Functionally, it has been reported that some types of neuropathic pain can be alleviated by blocking CCR1 expression with siRNA [11], and that the administration of a CCR1 antagonist can prevent some types of murine bone cancer pain [10] and partially reduce writhing responses in mice receiving intraperitoneal acetic acid or mechanical hyperalgesia in inflamed mice [14]. Among the different chemokines able to activate CCR1 [15], CCL3 (MIP-1a, macrophage inflammatory protein-1a) and CCL5 (RANTES, reduced upon activation normal T-cell expressed and secreted) are particularly related to nociception.…”

“…The stimulation of CCR1 expressed in nociceptors causes Ca 2+ influx and enhances capsaicin responsiveness [6], and the local administration of CCR1 agonists elicits nociceptive behaviours in mice [9,10]. CCR1 is up-regulated in sensory neurons [11] and the spinal cord [7,12] after nerve injury and increased CCR1 mRNA has also been measured in rats 24 hr after receiving carrageenan [13], supporting its involvement in nociceptive processing. Functionally, it has been reported that some types of neuropathic pain can be alleviated by blocking CCR1 expression with siRNA [11], and that the administration of a CCR1 antagonist can prevent some types of murine bone cancer pain [10] and partially reduce writhing responses in mice receiving intraperitoneal acetic acid or mechanical hyperalgesia in inflamed mice [14].…”

“…Among the different chemokines able to activate CCR1 [15], CCL3 (MIP-1a, macrophage inflammatory protein-1a) and CCL5 (RANTES, reduced upon activation normal T-cell expressed and secreted) are particularly related to nociception. CCL3 mRNA is up-regulated in the spinal cord of inflamed rats [16] and the spinal expression of CCL3 increases in mice with prostatitis [17] or nerve injury [11] being its neutralization with a specific antibody able to evoke analgesic effects [12]. CCL5 has been also previously related to hypernociceptive reactions associated with neuropathic injury [18] and tumour development [10,19,20].…”