Immune reactions and nerve repair in mice with sciatic nerve injury 14 days after intraperitoneal injection of Brazil

BALB/c mice were intraperitoneally injected with 10, 5 or 2.5 mg/kg Brazil for 14 days after sciatic nerve injury. Results demonstrate that the spleen T/B lymphocyte stimulation index and serum circulating immune complex concentration were significantly reduced, and the morphology of the soleus muscle was restored in mice with sciatic nerve injury. These effects of Brazil were dose-dependent. Our experimental findings indicate that Brazil can regulate immune responses after nerve injury and promote sciatic nerve repair.

LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes

Aim:The majority of preclinical studies investigating aberrant glial-neuroimmune actions underlying neuropathic pain have focused on male rodent models.Recently,studies have shown peripheral immune cells play a more prominent role than glial cells in mediating pathological pain in females.Here,we compared the onset and duration of allodynia in males and females,and the anti-allodynic action of a potentially novel therapeutic drug(BIRT377)that not only antagonizes the action of lymphocyte function-associated antigen-1(LFA-1)to reduce cell migration in the periphery,but may also directly alter the cellular inflammatory bias.Methods:Male and female mice were subjected to peripheral nerve injury chronic constriction injury(CCI)applying two methods,using either 4-0 or 5-0 chromic gut suture material,to examine potential sex differences in the onset,magnitude and duration of allodynia.Hindpaw sensitivity before and after CCI and application of intravenous BIRT377 was assessed.Peripheral and spinal tissues were analyzed for protein(multiplex electrochemiluminescence technology)and mRNA expression(quantitative real-time PCR).The phenotype of peripheral T cells was determined using flow cytometry.Results:Sex differences in proinflammatory CCL2 and IL-1βand the anti-inflammatory IL-10 were observed from a set of cytokines analyzed.A profound proinflammatory T cell(Th17)response in the periphery and spinal cord was also observed in neuropathic females.BIRT377 reversed pain,reduced IL-1βand TNF,and increased IL-10 and transforming growth factor(TGF)-β1,also an anti-inflammatory cytokine,in both sexes.However,female-derived T cell cytokines are transcriptionally regulated by BIRT377,as demonstrated by reducing proinflammatory IL-17A production with concurrent increases in IL-10,TGF-β1 and the anti-inflammatory regulatory T cell-related factor,FOXP3.Conclusion:This study supports that divergent peripheral immune and neuroimmune responses during neuropathy exists between males and females.Moreover,the modulatory actions of BIRT377 on T cells during neuropathy are predominantly specific to females.These data highlight the necessity of including both sexes for studying drug efficacy and mechanisms of action in preclinical studies and clinical trials.