Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity

Figure 1

Immunomodulatory mechanism exerted by neuropeptides in microglia exposed to a lipotoxic stimuli. (a) Microglia pro- and anti-inflammatory stimuli. In microglia, fatty acids and leptin can induce cytokine secretion through TLR4/IKK/NF-κB pathway, but only leptin can activate NF-κB through LepR/IRS1/AKT pathway. Also, leptin induces MHC class II expression leading to T lymphocytes activation. Cytokines have paracrine and autocrine effects. α-MSH inhibits the IκB degradation through MC4R and by blocking the LepR pathway through MC1R. Ghrelin blocks the TLR4/IKK/NF-κB pathway activation in microglia cells by indirect effects. (b) T lymphocyte activation. Microglia presents the antigen to CD4+ T cells and through the receptor complex MHCII/B7-TCR/CD28 these cells proliferate to the proinflammatory phenotype Th1 which produce IL-2 and INF-γ through PKCθ-CARMA-MALT1-Bcl10/NF-κB complex and by leptin action. (c) Astrocytes inflammatory mechanism. IL-1β induces the secretion of extracellular vesicles which inhibits PPARα expression on hepatocytes leading to TNF-α, IL-1β, and MCP-1 production facilitating lymphocyte infiltration to CNS. (d) Lymphocyte extravasation to CNS. Inflammatory signals such as cytokines and CMP-1 promote the expression of adhesion proteins E-selectin, P-selectin, and ICAM-1. Lymphocytes can interact with the adhesion proteins through its own integral proteins VLA-α4, PSGL-1, and LFA-1 and cross the BBB. Melanocortins prevent T-cell infiltration by the α-MSH-MC1R interaction which blocks externalization of adhesion proteins.