Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17(+/+)) and IL-17 knock-out (IL-17(-/-)) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17(-/-) mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor-α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17(-/-) mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.

Growing evidence suggests that leukocyte extravasation is initiated by the interaction of selectins with their ligands; as well as an essential role for P-selectin in the initial recruitment of inflammatory cells to sites of inflammation. In this study, P-selectin-deficient (P-sel-/-) mice were used to test the hypothesis that lack of P-selectin would attenuate the recruitment of inflammatory cells to the site of inflammation, thereby modulating pain in a murine chronic neuropathic pain model. Nociceptive sensitization and the microenvironment of the peripheral injury site were studied in wild-type (P-sel+/+) and P-selectin-deficient (P-sel-/-) mice after partial sciatic nerve ligation (PSNL). Variables measured included myeloperoxidase (MPO) activity, several inflammatory cell infiltration profiles, cytokines, and endogenous opioid peptide expression in damaged nerves. Results indicate that behavioral hypersensitivity, MPO activity, and infiltration of neutrophils and macrophages were attenuated in P-sel-/- mice after PSNL. Proinflammatory cytokines, tumor necrosis factor α, and interleukin (IL)-6, were reduced in damaged nerves following PSNL; however, several antiinflammatory cytokines - IL-1Ra, IL-4, and IL-10 - were significantly increased in P-sel-/- mice. In addition, endogenous opioid peptides mRNA was significantly lower in P-sel-/- mice compared with P-sel +/+ mice. The current results demonstrated that the absence of P-selectin in mice leads to an altered microenvironment that attenuated behavioral hypersensitivity. The specific role of P-selectin could have been a result of decreased neutrophils, as well as the accumulation of macrophages at the site of injury, which may subsequently modulate the inflammatory cytokine expression and impact behavioral hypersensitivity within the injured nerve.

CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5-aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI.