MR. WISITSAK PHOKSAWAT
Ph.D. candidated in Biomedical Sciences Program,
Graduate School, Khon Kaen University, Thailand.
Evidence of NKG2D/ ligands interaction promote Atherosclerosis
Advisor : Assoc. Prof. Dr. Chanvit Leelayuwat
Multi-risk factor of Atherosclerosis
Dyslipidemias
- high of low-density lipoprotein cholesterol (LDL-C)
- low of high-density lipoprotein (HDL)
Diabetes Mellitus and Impaired glucose tolerance (IGT)
Hypertension
Obesity and overweight
Cigarette smoking
Increased age, Gender, Family history and race
Involvement of abnormal metabolic conditions in atherosclerosis
abnormal metabolic conditions( Dyslipidemias)
Stress to artherial endothelial cells(up-regulated chemokine and adhesion molecules, recruit atherogenic
immune cells)
Vascular inflammation
Atherosclerosis(chronic inflamation and auto-immune
disease)
Initiation of atherosclerosis
Picture from Obesity, inflamation, and altherosclerosis. Nat Rav. Cardiol. (2009)
LDL oxidation
Nonenzymatic mechanisms
- the catalysis by transition metal ions, copper(Cu2+), iron(Fe2+),
and hemin (Fe3+)
- hemoglobin (Hb)
Enzymatic mechanisms
- myeloperoxidase
- 15 or 12/15-lipoxygenase (LO)
- NADPH oxidases
Classification of scarvenger receptors base on structural motifs(Krieger and colleagues, 1997)
• SR-AI/SR-AII, CD36, SRB1, MARCO, LOX1, SREC-1/SREC-II, SR-PSOX, Stabilin-1
recognize modified low-density lipoproteins.
Picture from Role of macrophage scavenger receptors in atherosclerosis, immunobiology (2012).
Schematic mechanisms of scavenger receptor mediated interaction with modified lipoproteins
I. Recognition of the ligand
II. Invagination of the membrane
forming vesicles
III. The degradation of modified
lipoprotein ligands in
lysosomes
Three steps are ;
Picture from Role of macrophage scavenger receptors in atherosclerosis, immunobiology (2012).
Picture from Obesity, inflamation, and altherosclerosis. Nat Rav. Cardiol. (2009)
T cells in altherosclerosis
• Macrophage can take up, process, and present neo-antigens such as oxLDL to CD4+ T cells.
• About 10 % of CD4+ T cells cloned from human lesion recognize oxLDL on MHC classII (DR).
Cytokines involvement in atherosclerosis
Pro-athergenic cytokines Anti-athergenic cytokines
TNF-αIL-1IL-1 βIL-2IL-12IL-18IFN-α
IFN-ɣ
TGF-βMCP-1RANTESCD40LIL-4 ?IL-6 ?
TGF-βIL-5IL-9IL-10IL-13IL-33
IL-1raIL-4 ?IL-6 ?
• Induce Pro-athergenic chemokine release• Activated adhesion molecules expression• Effects SMC migration and proliferation• Regulated immune responses promoting Th1 response• Stimulates MMP expression• Induces apoptosis• Modulates extracellular matrix expression
• Induce anti-athergenic chemokine release• Regulated immune responses promoting Th2 response• Stimulates profibrotic state promoting wound healing and angiogenesis
NKG2D receptor
• KLRK1 (killer cell lectin-like receptor subfamily K, member 1)
• encode on human chromosome 12 within NK gene complex and
chromosome 6 in mice
• Type II C-type lectin-like family of transmembrane proteins
• express as homodimer on NK cell, NKT cell, + T cell and some
CD8+ T cells
• function both an activating and co-stimulatory receptor
• bind to variety of ligands;
- Human : ULBP, RAET1, MICA,MICB
- Mouse : RAE1, H60, MULT1
Inhibitory and activating receptors of NK cells
• inhibitory receptors KIRs CD94/NKG2A ILTs • activating receptors CD16 NCRs KIR2DS CD94/NKG2C NKG2D
Upregulation of NKG2D Ligands in Sera and Atherosclerotic Plaques of patients with
Metabolic Dysfunction.
NKG2D ligands were up-regulated in atherosclerotic plaques
Both macrophage and endothelial cells of atherosclerotic plaques expressed MICA/B
* p<0.05 , ** p< 0.01 , *** p< 0.001
Preferential Upregulation of NKG2D Ligands in Tissue and Organs of
ApoE -/- Mice Where Abnormal Metabolites Accumulate
The ligands are up-regulated (10-30 fold)
in the atherosclerotic aortas.
NKG2D plays a critical role in plaque formation in Western diet (WD)–fed and streptozotocin(STZ) -diabetic apolipoprotein E–deficient (ApoE ¯/¯) mice.
Preventing NKG2D/Ligand Interactions Suppresses Plaque Formation in ApoE -/-Mice
(reduced 5-6 fold)
* p<0.05 , ** p< 0.01 , *** p< 0.001
Oil red O staining of cross sections of aortic roots also revealed significantly reduced plaque formation in Klrk1-/-ApoE-/- mice compared with the ApoE-/- controls
* p<0.05 , ** p< 0.01 , *** p< 0.001
Preventing NKG2D/Ligand Interactions Reduces the Systemic Production of Multiple Cytokine Markers Associated With Immune Activation
The NKG2D/ligand-mediated immune cell activation associated with atherosclerotic
progression might function at least partly through the increased production of these cytokines.
* p<0.05 , ** p< 0.01 , *** p< 0.001
Acknowledgement
Associate Professor. Dr. Chanvit Leelayuwat for my advisor.
Associate Professor. Dr. Nantarat Komanasin and Dr. Amornrat Jumniansong
Cardiovascular Research Group (CVRG), Khon Kaen University, Thailand.
The Higher Education Research Promotion and National Research
University Project of Thailand, Office of the Higher Education Commission, through
the Center of Exellence in Specific Health Problems in Greater Mekong Sub-region
Cluster (SHeP-GMS), Khon Kaen University (KKU).
All members of LAB3 and CVRG groups
Thank you for your attention
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