LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes
| العنوان: | LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes |
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| المؤلفون: | Mara A. Havard, Erin D. Milligan, Jacob E. Sanchez, Harrison T. West, Nikolaos Mellios, Nathan W. Harris, Arden G. Vanderwall, Jeffrey P. Norenberg, Shahani Noor, Melody S. Sun, Carsten R. Wagner, Lauren L. Jantzie, Monique Nysus |
| المصدر: | Neuroimmunology and neuroinflammation |
| بيانات النشر: | OAE Publishing Inc., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | neuroimmune, glia, peripheral immune, Lymphocyte, medicine.medical_treatment, T cell, Immunology, T cells, Neuropathic pain, Article, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, business.industry, FOXP3, Allodynia, medicine.anatomical_structure, Cytokine, Neurology, Peripheral nerve injury, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, 030215 immunology |
| الوصف: | 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-1β and 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-1β and 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. |
| تدمد: | 2349-6142 2347-8659 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6b4239255e02b07ab5c3095bd7e0df2Test https://doi.org/10.20517/2347-8659.2019.18Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e6b4239255e02b07ab5c3095bd7e0df2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23496142 23478659 |
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