The effects of 2-hydroxypropyl-β-cyclodextrin on hematopoiesis and the white adipose tissue

Abstract

The modern Western lifestyle offers many conveniences - sedentary routines, abundant processed food, and digital rather than in-person contact. Evolution has shaped the immune system for pathogen defense and has not adapted to sterile, lifestyle-related stimuli that fuel metaflammation, a chronic low-grade inflammatory condition in metabolic diseases. This inflammatory state accelerates non-communicable diseases (NCD), including atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is marked by cholesterol accumulation and immune cell infiltration in the arterial wall, and is profoundly shaped by metabolic and inflammatory imbalance.<br /> Here, we set out to determine whether the known antiatherosclerotic effects of 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cyclic oligosaccharide, can be explained through its effects on the white adipose tissue (WAT), a key site of metaflammation. We further aimed to investigate potential effects on the hematopoietic phenotype, specifically whether HPβCD counteracts Western diet (WD)-induced myeloid reprogramming in the bone marrow, with a particular focus on the monocytic progenitor lineage, which is known to enter both the adipose tissue and the arterial wall, thereby promoting inflammatory disease progression.<br /> We used two derivates of HPβCD with different degree of substitution, HPβCD-HP5 and HPβCD-HP7, in an <em>Apoe</em>^-/- atherosclerosis mouse model. The data show significant reduction in atherosclerotic plaque burden in male, but not female mice, accompanied with reduced cholesterol and increased oxysterol levels, in both a prevention and therapeutic setting. In the prevention study, both HPβCD increased fibroblast growth factor 21 (FGF21) levels and reduced the frequency of adipose tissue macrophages (ATM) in the gonadal WAT (gWAT) which was associated with reduced adipocyte size.<br /> In summary, our study demonstrates that the investigated HPβCD derivatives modulate adipose tissue morphology, reduce ATM, and stimulate FGF21 secretion from gWAT in a sex-dependent manner. Together, these findings offer new insights into how cyclodextrins may influence metabolic inflammation as an atheroprotective effect. They also highlight the importance of considering sex as a biological variable in preclinical research.