Flavonoids and macrophage polarization: Key players in the immunomodulation of cardiometabolic syndrome and related therapies

Abstract

Cardiometabolic syndrome (CMS) is a major public health challenge characterized by obesity, insulin resistance, hypertension, and chronic inflammation, which increase the risk of type 2 diabetes (T2D) and cardiovascular disease. In this context, inflammatory M1 macrophages are pivotal, as they produce proinflammatory cytokines and contribute to oxidative stress, insulin resistance, and lipid accumulation in adipose tissue. Polyphenols with anti-inflammatory, antioxidant, and antiobesity properties alleviate CMS by promoting M2 macrophage differentiation and reprogramming M1 macrophages toward the M2 phenotype. Flavonoids inhibit inflammatory pathways such as NF-kB and activator protein-1 (AP-1); reduce the expression of proinflammatory markers such as TLR4, NOD-like receptor family pyrin domain-containing 3 (NLRP-3), and inducible nitric oxide synthase (iNOS); and enhance anti-inflammatory responses, including IL-10, Nrf-1, and peroxisome proliferator-activated receptor (PPAR) expression. They prevent foam cell formation by decreasing LPX-1, CD36, scavenger receptor-A, B1, and LOX-1 expression while increasing ABCA1 and ABCG1 levels. Flavonoids are antiobesity agents that decrease the infiltration of macrophages in adipose tissue and suppress the M1 phenotype in adipose tissue macrophages, lowering inflammation and leading to the suppression of lipogenesis and stimulation of lipolysis in adipocytes. This review highlights the importance of macrophage activation in metabolic imbalance and the potential of flavonoids in treating CMS through the induction of M2 macrophages.