Abstract Background Chronic High Fat Diet (HFD) drives adverse metabolic consequences and hyperactivates Granulocyte-Monocyte Progenitors (GMPs) leading to supra-physiological neutrophil production during systemic inflammation. Being short-lived cells, neutrophil egress from the bone marrow (BM) is tightly regulated by CXCR4 receptor. Purpose We sought to determine whether short-term HFD exposure imprints lasting changes in the GMP transcriptomic profile and alters activation and migration markers in mature circulating neutrophils. Furthermore, we aimed to verify if this process depends on CXCR4 signaling. Methods We studied the metabolic and the immunophenotypic profiles of WT mice fed HFD (60% Kcal from fat) for seven days (short-term HFD), a markedly shorter exposure compared to the multi-month regimen typically used to induce pronounced dysmetabolic adaptations. We measured the prandial profile of surrogate indicators of systemic metabolic adaptations to short-term HFD feeding and assessed the membrane expression of activation and migration markers in mature circulating neutrophils by flow-cytometry. To determine whether neutrophil phenotypic changes reflected altered mobilization towards peripheral tissues, we quantified plasma proteins involved in neutrophils behavior using untargeted plasma proteomics. Moreover, to study if long-lasting effects on BM progenitors occur after short-term HFD feeding, we characterized the transcriptomic profile of isolated GMPs by bulk RNA-seq after exposure to short-term HFD followed by re-feeding with standard chow diet. Finally, to explore the involvement of CXCR4 signaling in altered neutrophil dynamics, we studied the immune-metabolic adaptations of mice harboring neutrophil specific deletion of CXCR4 (CXCR4fl/flMrp8Cre+) versus wild-type counterpart (CXCR4fl/flMrp8Cre-). Results Short-term HFD feeding resulted in dysmetabolic impact and activated inflammatory and innate immune pathways, together with redistribution of BM neutrophil progenitor subsets and altered transcriptomic profile. This resulted in increased circulating neutrophil count in CXCR4fl/flMrp8Cre-. By contrast, CXCR4fl/flMrp8Cre+ mice displayed persistent neutrophilia, independent from the metabolic adaptations. However, reduced membrane expression of CXCR4 and CD62L along with increased expression of CD11b was independent from the presence of CXCR4 in neutrophils, suggesting a phenotypic remodeling toward enhanced migratory and activated features, independent from the neutrophilia and CXCR4 expression. However, from a metabolic point of view, this derailed neutrophil behavior impacted surrogate markers of systemic metabolism, including triglyceridemia and insulin, in the CXCR4fl/flMrp8Cre+ model. Conclusions Short-term HFD feeding drives a neutrophil-skewed immune response and long-lasting reprogramming of BM progenitors, suggesting CXCR4-dependent neutrophil-specific pathways as key regulators of metabolic adaptation to dietary fats.
Parolini et al. (Fri,) studied this question.