Targeting the [beta]2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure

Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1[be...

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Bibliographic Details
Published in:Acta neuropathologica communications 2019-04, Vol.7 (1)
Main Authors: Sanchez, Joshua J, Sanchez, Jacob E, Noor, Shahani, Ruffaner-Hanson, Chaselyn D, Davies, Suzy, Wagner, Carston R, Jantzie, Lauren L, Mellios, Nikolaos, Savage, Daniel D, Milligan, Erin D
Format: Article
Language:English
Subjects:
Analysis
Antigens
Back pain
Cytokines
Development and progression
Health aspects
Immune system
Immunohistochemistry
Integrins
Interleukins
Lymphocytes
Messenger RNA
Microscopy
Novels
Pain management
Polyneuropathies
Pregnant women
Risk factors
RNA
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Summary:Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1[beta] protein expression. Additionally, the [beta]2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated. Here, we examine whether PAE increases the proinflammatory immune environment at specific anatomical sites critical in the pain pathway of chronic sciatic neuropathy; the damaged sciatic nerve (SCN), the dorsal root ganglia (DRG), and the spinal cord. Additionally, we examine whether inhibiting LFA-1 or IL-1[beta] actions in the spinal cord (intrathecal; i.t., route) could alleviate chronic neuropathic pain and reduce spinal and DRG glial activation markers, proinflammatory cytokines, and elevate anti-inflammatory cytokines. Results show that blocking the actions of spinal LFA-1 using BIRT-377 abolishes allodynia in PAE rats with sciatic neuropathy (CCI) of a 10 or 28-day duration. This effect is observed (utilizing immunohistochemistry; IHC, with microscopy analysis and protein quantification) in parallel with reduced spinal glial activation, IL-1[beta] and TNF[alpha] expression. DRG from PAE rats with neuropathy reveal significant increases in satellite glial activation and IL-1[beta], while IL-10 immunoreactivity is reduced by half in PAE rats under basal and neuropathic conditions. Further, blocking spinal IL-1[beta] with i.t. IL-1RA transiently abolishes allodynia in PAE rats, suggesting that IL-1[beta] is in part, necessary for the susceptibility of adult-onset peripheral neuropathy caused by PAE. Chemokine mRNA analyses from SCN, DRG and spinal cord reveal that increased CCL2 occurs following CCI injury regardless of PAE and BIRT-377 treatment. These data demonstrate that PAE creates dysregulated proinflammatory IL-1[beta] and TNF[alpha] /IL-10 responses to minor injury in the sciatic-DRG-spinal pain pathway. PAE creates a risk for developing peripheral neuropathies, and LFA-1 may be a novel therapeutic target for controlling dysregulated neuroimmune actions as a consequence of PAE. Keywords: Neuropathic pain, Prenatal alcohol exposure, Glia, Neuroimmune function, Peripheral immune system, Spinal cord
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-019-0701-y