Functional Recovery after Peripheral Nerve Injury is Dependent on the Pro-Inflammatory Cytokines IL-1β and TNF: Implications for Neuropathic Pain

Abstract

IL-1␤ and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate that mRNA and protein levels of IL-1␤ and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1␤ and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1␤ or TNF at the site of sciatic nerve injury in IL-1␤-and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1␤-, TNF-, and IL-1␤/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic nerve distal stump of mice lacking both IL-1R1 and TNFR1. Systemic treatment of mice with an anti-Ly6G antibody to deplete neutrophils, cells that play an essential role in the genesis of neuropathic pain, did not affect recovery of neurological function and peripheral axon regeneration. Together, these results suggest that targeting specific IL-1␤/ TNF-dependent responses, such as neutrophil infiltration, is a better therapeutic strategy for treatment of neuropathic pain after peripheral nerve injury than complete blockage of cytokine production.

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

“…This indicated that the algogenic effect of microgliaderived MVs was mediated, at least partly, by IL-1β. This is in agreement with previous reports that IL-1β acts as a mediator of supraspinal circuits of pain in neuropathic conditions [46][47][48].…”

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

“…Quantification of the Ly6C hi and Ly6C lo monocyte subsets supported the premise that the anti-Ly6G treatment did not affect any of them, indicating that 1A8 specifically depletes circulating neutrophils and spares the monocyte populations (Fig. 3E, 3F), in agreement with previous reports (43,48). As a point of interest, the administration route was a critical factor for keeping mice healthy in depletion experiments.…”

“…For multicolor immunofluorescent labeling, cells were incubated on ice with mouse Fc block (i.e., purified anti-mouse CD16/CD32; BD Biosciences) for 15 min to prevent nonspecific binding, followed by labeling for 30 min on ice with the following fluorescently conjugated primary Abs (all from BD Biosciences except where noted): anti-CD45 PerCP (dilution, 1:100), anti-CD11b Alexa Fluor 700 (1:100), anti-Ly6C BD Horizon v450 (1:167), anti-Ly6G PE-Cy7 (1:100), anti-F4/80 allophycocyanin (1:25), anti-CD3e PE-CF594 (1:100), and anti-7/4 PE (1:40, AbD Serotec) (for a full description of some of these primary Abs, please refer to our published work; see Ref. 43). As for the blood samples, the Live/Dead fixable yellow dead cell stain kit (Life Technologies) was used to distinguish live from dead cells.…”

Contribution of Inflammation to Chronic Pain Triggered by Nerve Injury

“…Neutrophils are the first immune cells migrating towards the injury site. Their numbers peak at 24 hours following peripheral nerve injury and decrease progressively after three days post-injury, but still remain significant for at least one week (Nadeau et al, 2011). Infiltrated neutrophils in injured nerves play an important role at the very early stages of neuropathic pain through the release of pro-inflammatory mediators, such as cytokines TNF-, IL-1 and IL-6 and reactive oxygen species, which are involved in regulating neuronal excitability (Schafers et al, 2003).…”

“…Systemic treatment of sciatic nerve injured mice with a monoclonal antibody against the Ly6G antigen specifically expressed by neutrophils demonstrated that depletion of neutrophils attenuates the development of neuropathic pain behaviour (Nadeau et al, 2011). Furthermore, using molecular and pharmacological approaches, partial or complete depletion of macrophages yield beneficial effects in alleviating nerve injury associated chronic pain.…”