Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation
成果类型：
Article
署名作者：
Hata, Masayuki; Andriessen, Elisabeth M. M. A.; Hata, Maki; Diaz-Marin, Roberto; Fournier, Frederik; Crespo-Garcia, Sergio; Blot, Guillaume; Juneau, Rachel; Pilon, Frederique; Dejda, Agnieszka; Guber, Vera; Heckel, Emilie; Daneault, Caroline; Calderon, Virginie; Des Rosiers, Christine; Melichar, Heather J.; Langmann, Thomas; Joyal, Jean-Sebastien; Wilson, Ariel M.; Sapieha, Przemyslaw
署名单位：
Universite de Montreal; Universite de Montreal; Universite de Montreal; Universite de Montreal; Universite de Montreal; Universite de Montreal; Universite de Montreal; Institut de Recherche Clinique de Montreal (IRCM); Universite de Montreal; Universite de Montreal; University of Cologne; University of Cologne
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-13544
DOI：
10.1126/science.abj8894
发表日期：
2023-01-06
页码：
45-61
关键词：
creb-binding-protein
macular degeneration
adipose-tissue
fatty-acids
AGE
inflammation
accumulation
progression
activation
expression
摘要：
Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.