Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component

Abstract

Supplemental Digital Content is Available in the Text.Inhibitors of leukocyte elastase inhibit spontaneous and evoked pain behaviors in mouse models of chronic pain of neuropathic, cancer, and diabetic origins.

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

“…First, a recent study reported little, if any, CD2-positive cells (presumably T cells) in the SC-DHs over 6 weeks after spared nerve injury (SNI) in adult rats [98], with the same experimental settings as in the seminal study concerning the roles of T cell infiltration into the SC-DHs in nerve injury-induced chronic tactile allodynia [85]. Moreover, another recent study reported little, if any, CD3-positive T cells in the SC-DHs 8 and 28 days after SNI in adult C57BL/6 male and female mice [99]. In our previous study, we also did not find any convincing evidences for the presence of αβ T cells in the SC-DHs 1 weeks after tibial nerve transection (TNT) in adult male Sprague-Dawley (SD) rats [15].…”

“…Fourth, after chronic constriction injury (CCI) to the sciatic nerves of adult male rats, very low densities of αβ T cells relative to the volume of the SC-DHs were detected in the ipsilateral SC-DHs in statistical sense [96,[102][103][104]. Finally, no CD3-positive T cells were found to significantly infiltrate into the SC-DHs in adult male or female rat or mice models of CIPN or PDN even for long-term durations [82,83,99,104].…”

“…Currently, it has been shown that the infiltration of T cells (CD3 positive) into the injured nerves is a general and intrinsic process in response to rodent or human mechanical or non-mechanical nerve injuries [99,100,112,113]. However, there are contrasting evidences showing that CD3-positive T cells do not significantly infiltrated into the injured nerves in adult C57BL/6 J male or female mice of CIPN or PDN [82,99]. To go further, αβ T cells have been conclusively found to infiltrate into the injured nerves after CCI or chronic mild compression and Fig.…”

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…Conversely, an inhibitor of granzyme B, serpinA3N, is produced by DRG neurons after peripheral nerve injury (Vega-Avelaira et al, 2009) where it is thought to attenuate mechanical allodynia in mice by inhibition of another serine protease, leukocyte elastase (Vicuna et al, 2015). Treatment of mice with small molecule inhibitors of leukocyte elastase after nerve injury temporarily reduced established neuropathic mechanical allodynia (Bali and Kuner, 2017). Furthermore, serpinA3N is capable of rescuing human fetal neuronal cell death mediated by anti-CD3 and anti-CD28 activated T cells (Haile et al, 2015).…”

“…Peripheral nerve injury recruits CD8 + T cells to the injured sciatic nerve (Hu et al, 2007;Bali and Kuner, 2017) where expression of antigen-presenting MHC class I molecules are increased (Bombeiro et al, 2016). Although sensory neurons express IFN-γ receptors (typically required for MHC I induction) they fail to upregulate MHC class I in response to IFN-γ signaling (Turnley et al, 2002).…”