A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity

Abstract

Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.

Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD

“…In this study, we performed a panoramic database mining analysis on microarray data of both human NASH and We attempted to integrate all the findings presented here, our papers, and others' reports and proposed a novel working model of multiple-hit TI model (Figure 7) with enhanced inflammation for NASH/NAFLD development with a synergy between hyperlipidemia induced by HFD feeding and hypomethylation induced by nutrient and gene deficiencies related to methionine-homocysteine circle as we reported [84][85][86][87][88][89][90][91]. Hyperlipidemia and NAFLD are highly associated [1,[92][93][94][95][96]. HFCD model upregulated significantly TI enzymes and lipid peroxidation enzymes but did not significantly upregulate cytokines, chemokines, and canonical and noncanonical inflammasome regulators.…”

Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators

“…These diseases and cell types were (a) three types of AIs such as lung injury (whole blood), septic shock (whole blood), and severe trauma (monocytes, leukocytes, and T cells); (b) nine types of MDs including obesity (adipocytes and adipose stem cells) and metabolically healthy obesity (MHO; subcutaneous adipose). Based on the criteria, patients with MHO have no metabolic syndrome (MetS) and insulin resistance (IR) ( 20 ) and are metabolically unhealthy obese (MUO; subcutaneous adipose). The difference between MUO and MHO can be found as cited ( 79 ), obese with IR (adipocytes), obese with insulin sensitivity (IS) (adipocytes), type 2 diabetes (T2D; liver, skeletal muscle, subcutaneous adipose, and visceral adipose), atherosclerosis (carotid artery plaques, macrophages, and T cells), atherosclerosis and familial combined hyperlipidemia (FCH; plaques and monocytes), and familial hypercholesterolemia (FHC; lymphoblastic cells); (c) seven types of ADs including rheumatoid arthritis (RA; macrophages), acute cutaneous lupus (ACLE; skin), chronic cutaneous lupus (CCLE; skin), psoriasis (skin), subacute cutaneous lupus (SCLE; skin), ulcerative colitis (UC; colon/rectum and PBMCs), and Crohn's disease (CD; PBMC); and (d) four types of organ failures (OFs) such as heart failure (left ventricle), hepatitis B virus-associated acute liver failure (liver), end-stage renal failure (ESRF; whole blood), and chronic kidney disease (CKD) hemodialysis (PBMC).…”

“…We and others recently reported that CVD stressors and risk factors such as hyperlipidemia (3,4), hyperglycemia (5), hyperhomocysteinemia (6,7), and chronic kidney disease (8)(9)(10) promote atherosclerosis and vascular inflammation via several mechanisms. These mechanisms include innate immune activation (11) of endothelial cells (ECs) (3,(12)(13)(14)(15) promoting EC injury (16); Ly6Chigh inflammatory mouse monocyte and CD40 + human monocyte differentiation (7,(17)(18)(19); disease reprogrammed macrophages (20)(21)(22); cytokine and secretome regulation (23)(24)(25)(26)(27)(28)(29)(30); decreased/transdifferentiated CD4 + Foxp3 + regulatory T cells (Treg) (24,(31)(32)(33)(34); and impaired vascular repairability of bone marrow-derived progenitor cells (35,36). In addition, we recently proposed new models such as intracellular organelle dangers (37) and reactive oxygen species (ROS) as an integrated sensing system for metabolic homeostasis and alarming (38), which indicated that metabolic reprogramming and dysfunction trigger mitochondrial (MT) ROS (4,(39)(40)(41...…”

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

“…Our results have provided novel insights into aortic endothelial cell (EC) activation, formulated an EC biology knowledge-based transcriptomic profile strategy, and identified new targets for the future development of therapeutics for cardiovascular diseases, inflammations, immune diseases, transplantation, aging, and cancers. One limitation of all the RNA-Seq data analyses is that due to the low-throughput nature of verification techniques in every laboratory, including ours, we could not verify every result we found with the analyses of high-throughput data, which are similar to all the studies with RNA-Seq (19,59), single-cell RNA-Seq, metabolomics (23), chromatin immunoprecipitation (CHIP)-Seq (24,44), and other-omics data (11,138,139). We acknowledge that carefully designed in vitro and in vivo experimental models will be needed in the future to verify the LPI-upregulated genes further and the underlying mechanisms we report here (9,140).…”

“…The activation of endothelial cells (ECs) is the earliest event and a central pathological process associated with the onset of atherosclerosis. Based on our previous findings, we propose that:(1) ECs are innate immune cells ( 3 – 5 ), as they display innate immune functions similar to those of prototypical innate immune cells, such as macrophages ( 5 , 10 , 11 ) and monocytes ( 12 – 18 ). (2) In addition to increased secretion of cytokines and chemokines and upregulation of adhesion molecules, activated ECs also exhibit two new hallmarks of innate immune cells, namely, upregulation of both danger-associated molecular patterns (DAMPs) receptors and major histocompatibility complex (MHC) molecules for antigen presentation ( 19 ).…”