myelin-oligodendrocyte-glycoprotein-(35-55) and Obesity

Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation

Topics: Animals; ATP Citrate (pro-S)-Lyase; Cells, Cultured; Cytokines; Diet, High-Fat; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Obesity; Peptide Fragments; Peritonitis; Phenotype; Signal Transduction

Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity-associated rises in TNF-alpha, IL-6 and TGF-beta are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T-cell sublineage, a subset with prominent pro-inflammatory roles. T-cells from diet-induced obese mice expand Th17 cell pools and produce progressively more IL-17 than lean littermates in an IL-6-dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet-induced obese mice developed more severe early disease and histopathology with increased IL-17(+) T-cell pools in target tissues. The well-described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

Topics: Animals; Colitis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Glycoproteins; Interleukin-17; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Obesity; Peptide Fragments; T-Lymphocytes, Helper-Inducer; Trinitrobenzenesulfonic Acid