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Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in
Mario Delgado1, G Miller Jonakait, Doina Ganea
1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Abstract:
Microglia react to even minor disturbances in CNS homeostasis and function as critical regulators of CNS inflammation. Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders. Microglia-derived inflammatory chemokines recruit various populations of immune cells, which initiate and maintain the inflammatory response against foreign antigens. Entry and retention of activated immune cells in the CNS is a common denominator in a variety of traumatic, ischemic, and degenerative diseases. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two structurally related neuropeptides that function as potent anti-inflammatory factors in the periphery. Here we investigated the effects of VIP and PACAP on chemokine production by activated microglia. VIP and PACAP inhibit the expression of the microglia-derived CXC chemokines MIP-2 and KC, and of the CC chemokines MIP-1alpha, -1beta, MCP-1, and RANTES. The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP/PACAP on NFkB binding. The VIP/PACAP inhibition of both chemokine production and of NFkB binding is mediated through the specific receptor VPAC1 and involves a cAMP-dependent intracellular pathway. Of biological significance is the fact that the inhibition of chemokine production by VIP/PACAP leads to a significant reduction in the chemotactic activity generated by activated microglia for peripheral leukocytes, i.e., neutrophils, macrophages, and lymphocytes. Because reduction in the number and activation of infiltrating leukocytes represents an important factor in the control of inflammation in the CNS, VIP and/or PACAP released by neurons during an inflammatory response could serve as neuronal survival factors by limiting the inflammatory process.
Insights
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) reduce neuroinflammation by inhibiting microglia-derived chemokines. These neuropeptides limit immune cell infiltration, potentially protecting neurons in CNS disorders.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Cellular Neuroscience
Background:
- Microglia are key regulators of central nervous system (CNS) inflammation, releasing chemokines that recruit immune cells.
- Immune cell infiltration into the CNS is implicated in various neurological diseases.
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are known peripheral anti-inflammatory neuropeptides.
Purpose of the Study:
- To investigate the effects of VIP and PACAP on chemokine production by activated microglia.
- To elucidate the molecular mechanisms underlying VIP and PACAP's anti-inflammatory actions in the CNS.
Main Methods:
- Primary microglia cultures were activated, and the effects of VIP and PACAP on chemokine gene expression were analyzed.
- NF-kB binding activity was assessed to determine the impact on inflammatory signaling pathways.
- Chemotactic activity assays were performed to evaluate the functional consequences of VIP/PACAP treatment.
Main Results:
- VIP and PACAP significantly inhibited the expression of multiple microglia-derived CXC and CC chemokines (MIP-2, KC, MIP-1α, MIP-1β, MCP-1, RANTES).
- This inhibition of chemokine gene expression correlated with reduced NF-kB binding activity.
- VIP/PACAP treatment diminished the chemotactic activity of activated microglia for peripheral leukocytes, including neutrophils, macrophages, and lymphocytes.
Conclusions:
- VIP and PACAP exert potent anti-inflammatory effects on microglia by suppressing chemokine production via a VPAC1 receptor and cAMP-dependent pathway.
- By reducing immune cell recruitment, VIP and PACAP may act as neuroprotective factors in CNS inflammatory conditions.
- These findings highlight the therapeutic potential of VIP and PACAP in managing neuroinflammatory and neurodegenerative diseases.