From PLP1 Misfolding to Oligodendrocyte Degeneration: A Proteostasis-Centered Framework for Pelizaeus-Merzbacher Disease.

Obesity is associated with several comorbid diseases and conditions including impaired glucose tolerance, fatty liver disease, coronary artery disease and some types of cancer []. Some of these conditions (e.g. type 2 diabetes mellitus, T2DM) are at least in part the consequence of a chronic tissue inflammation triggered by macrophages that accumulate in adipose tissue (adipose tissue macrophages, ATM) and release inflammatory mediators []. Importantly, the NLR family pyrin domain containing 3 (NLRP3) inflammasome seems to be involved in this process. It has been demonstrated that obesity is related to the assembly and activation of the NLRP3 inflammasome and caspase 1 cleavage, ultimately resulting in the maturation of the proinflammatory cytokines IL-1β and IL-18 []. Peripheral blood monocytes differentiate into macrophages after immigration into the tissue and are a major source of macrophages in adipose tissue in particular [–]. The attraction of monocytes to adipose tissue is mediated by the monocyte chemoattractant protein-1 (MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) [, ]. Peripheral blood monocytes are increased in people with obesity [, ], and immigrate into adipose tissue in increased numbers, and this effect is most prominent in visceral adipose tissue []. Monocytes are not a homogenous population, but consist of three major subpopulations: classical monocytes (CD14/CD16), intermediate monocytes (CD14/CD16) and non-classical monocytes (CD14 /CD16 + ) []. Of particular interest are intermediate monocytes: This subpopulation is associated with several inflammatory rheumatic diseases, ageing and coronary artery disease (CAD) [–]. The classical monocytes harbor another small subpopulation, the CD14/CD56 monocytes which are expanded in autoimmune diseases such as rheumatoid arthritis (RA) and Crohn’s disease. They produce more reactive oxygen intermediates and pro-inflammatory cytokines in RA and are more efficient antigen-presenting cells [, ].