Toll-like receptor 2 (TLR2) regulates neutrophil production in diet-induced obesity

Abstract

BACKGROUND: Obesity has become increasingly prevalent due to over-nutrition and sedentary lifestyle. While many past studies have identified a link between metabolic dysfunction and tissue inflammation, molecular mechanisms that initiate and propagate inflammation remain unclear. In this study, we investigated the role of Toll-like receptor-2 (TLR2) in modulating inflammatory response in mice and examined the effect of high-fat diet (HFD)-induced myelopoiesis and systemic inflammation. OBJECTIVE: To investigate the role of TLR2 in regulating the HFD-induced myelopoiesis and systemic inflammation. METHODS: After HFD-feeding for 12 weeks, mouse bone marrow (BM) cells and peripheral blood leukocytes were isolated. Mouse BM hematopoietic progenitor cells (HSPCs) were enriched using a HSPC enrichment kit. Isolated HSPCs were used for RNA purification, FACS analysis, and RT-qPCR. Statistical analysis was performed on FACS and RT-qPCR data. RESULTS: Compared to WT mice, TLR2 KO mice demonstrated significant reduction in the mRNA expression in HSPCs of C/EBPα, C/EBPε, GFI-1, PU.1, and Runx1, which are all transcription factors involved in myeloid cell differentiation. FACS analysis showed a substantial percentage reduction in BM neutrophils and increase in BM lymphocytes in TLR2 KO mice in comparison to WT mice. Interestingly, the percentage of blood B-lymphocyte of TLR2 KO mice was also markedly decreased. CONCLUSIONS: HFD feeding activates TLR-dependent C/EBPα-GFI-1 pathway required for myelopoiesis and systemic inflammation. Given that the deletion of TLR2 is sufficient to reverse the long-term HFD-induced molecular changes and neutrophil production, TLR2 may be involved in obesity-related systemic tissue inflammation.