Lipid metabolism disorders and immune metabolic programming in patients with idiopathic multicentric Castleman disease

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder characterized by lymphadenopathy, with high heterogeneity in clinical manifestations. The metabolic profile of patients with iMCD remains poorly characterized. Here, we demonstrate that serum cholesterol levels are significantly reduced in patients with iMCD, correlating with disease severity and prognosis; yet intracellular cholesterol acquisition is markedly upregulated in key immune subsets, particularly B cells and T cells. To assess the prognostic implications of serum lipid indicators,we analyzed survival in all patients with iMCD.On univariable analysis decreased total cholesterol (TC) was associated with poorer progression-free-survival. We found that TC (p = 0.012) significantly decreased in patients with severe iMCD compared to patients with mild iMCD. We further performed proteomic analysis on patients' sera, yielding consistent conclusion. The results demonstrated that patients with iMCD exhibited marked depletion of proteins associated with lipid metabolism, particularly cholesterol transport proteins, compared to healthy donors. Cholesterol metabolism was significantly downregulated in patients with iMCD, accompanied by suppression of cholesterol transport-related pathways. In summary, these characteristics imply the potential role of serum cholesterol indicators to be markers for prognosis and disease severity. We speculate that the significant decrease of serum cholesterol level and marked depletion cholesterol transport proteins in patients with iMCD may mirror profound metabolic reprogramming in immune cells, which may coordinate immune responses during inflammation. To delineate the landscape of metabolic reprogramming in peripheral blood immune cells (PBMCs) from iMCD patients and identify the potential role of cholesterol metabolism on immune cells, we analyzed the single-cell transcriptome atlas of PBMC from 15 patients with iMCD and 4 healthy donors, focusing on the metabolic alteration. The results indicated that PBMCs in iMCD underwent various metabolic reprogramming, especially activation of numerous lipid metabolism pathways in B cells in iMCD. Based on clinical results, we focused our study on cholesterol metabolism. Intriguingly, the findings revealed that PBMCs in iMCD showed elevated cholesterol acquisition. We classified PBMCs into 31 cell subsets to further identify the cholesterol preference of each immune population in iMCD. The results demonstrated enhanced cholesterol accumulation across diverse immune cell populations in iMCD. Notably, key inflammatory effector cells, including B cells, T cells, exhibited markedly increased cholesterol acquisition. To understand how intracellular cholesterol acquisition may interact with immune response of PBMCs, we further calculated the relationship between serum cytokines and serum lipid levels. Through stratifying patients with iMCD into low-lipid group and high-lipid group by serum lipid indicators, we found that decreased level of serum lipid was significantly linked to high level of interleukin-12P70 (IL-12). Previous studies have reported that IL-12 can amplify IFN-γ production [1] , so we explored whether IL-12 promotes IFN-γ secretion in iMCD. Single-cell sequencing showed that IL-12 was predominantly expressed in B cells and IL-12 receptor was markedly higher in T/NK/NKT cells. Building on our previous report that NK/NKT cells amplifies the pro-inflammatory activity of CCL monocytes via IFN-γ secretion, we proposed that IL-12 confers IFN-γ-secreting capacity to T/NK/NKT cells. In summary, our data suggest that serum lipid levels, especially serum total cholesterol level, may be prognostic and severity makers. We speculate that immune-driven cells, particularly B cells and T cells, undergo cholesterol acquisition to support their hyperactivated inflammatory through crosstalk with cytokine signals. [1] Yin X, Liu Y, Ding S, Ge J, Yang M, Wang Z, Lv Z, Luo X, Ma L, Yu W, Wei J, Yang C, Yao Q, Zhu L, Zhao S, Chen Y, Meng H, Jin J, Tong H, You L. IFN-γ promotes the progression of iMCD by activating inflammatory monocytes. Blood. 2025 Jul 3;146(1):76-88. doi: 10.1182/blood.2024027689. PMID: 40163892.