Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation

Abstract

Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.

SARS-CoV-2 Infection Is Associated with Reduced Krüppel-like Factor 2 in Human Lung Autopsy

“…Furthermore, a comparison to other respiratory viruses, such as influenza, would be necessary to assess the specificity of vasculopathy in COVID-19, or whether vasculopathy is a general phenomenon of virally-induced lung injury. Lastly, KLF2 is implicated in the development of metabolic diseases such as obesity and coronary artery disease (13,14), and may regulate innate immunity in humans (15), but whether the diseases themselves regulate KLF2 is unknown. Immune suppression via corticosteroids is now used to treat severe COVID-19 pneumonia (16).…”

Evolutionary Protection of Krüppel-Like Factors 2 and 4 in the Development of the Mature Hemovascular System

“…Through its negative regulation of NFkB-mediated transcription, KLF2 resists inflammatory activation in monocytes, macrophages, and neutrophils (42)(43)(44)(45). Much like its endothelial counterpart, myeloid KLF2 levels are sensitive to inflammatory stimuli and are decreased in acute and chronic inflammatory states such as sepsis, coronary artery disease, and metabolic disease (42,45,46). The downstream effects of lost KLF2 expression are multitudinous.…”

“…The downstream effects of lost KLF2 expression are multitudinous. Loss of KLF2 in macrophages affects the transcription of >1,400 genes, encompassing a wide range of pathways such as metabolism, chemotaxis, and cytokine release (46). This underscores the profound regulatory effect that KLF2 has on local and systemic inflammatory states.…”

“…When myeloid cell activation chronically persists, however, inflammatory diseases arise. Unsurprisingly, mice with myeloid-specific deletion of KLF2 are more susceptible to diseases such as atherosclerosis, metabolic disease, neurodegeneration, and shock (32,(45)(46)(47)(48). Protection of myeloid KLF2 expression across the lifespan and generations, therefore, is critical in the prevention of aberrant inflammation and resultant diseases.…”

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

“…For multivariate analysis, patient clinical information was retrieved from Supplemental GSE149119 murine bone marrow-derived macrophage Klf2-knockout (45) Dusp6 expression between vehicle and KO were compared with Mann-Whitney U-test GSE27602 murine Klf2-/-yolk sac erythroid cells (46) Multi-Chip Significance score (S-score) and expression comparison p-value of Dusp6 (probe 1415834_at) between WT and Klf2-/-samples were identified. As per source publication, probe with absolute S-score values greater or equal to 2.00 were considered to be significant.…”