Effect of Cow Milk-Derived Extracellular Vesicles on Arthritis. Fons van de Loo
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1 Effect of Cow Milk-Derived Extracellular Vesicles on Arthritis Fons van de Loo
2 Rheumatoid arthritis (RA) Multifactorial, chronic inflammatory disease Affects 1-2% of world population Symptoms: Pain Immobility Disease characteristics: Synovial inflammation Cartilage destruction Bone destruction Strand et al. Nature Reviews Drug Discovery 6, (January 2007)
3 RA is a complex multifactorial disease Lifestyle Environment 70-80% EBV Odds ratio 2.0 men Odds ratio 5.47 DIET Age Peridontitis and RA odds ratio 1, % Sex F:M 3:1 Role of food components, protective or deleterious?
4 Claims of foods that fight RA Mediterranean diet, less meat.. more vegetables and olive oil Fish, omega-3 fatty acids A meta-analysis published in Archives of Medical Research 43 (2012) shows that Omega-3 PUFAs reduces NSAID consumption by RA patients. Most likely an effect on pain!
5 Milk is not just food Energy Protein Fat Lactose Salt Calcium 130 kcal 7 gram 3,5 gram 9 gram 0,05 gram 0,25 gram Human breast milk contains anti-microbial and immune development compounds 1, 2 Extracellular vesicles, including exosomes, are present in human breast milk and bovine colostrum 3, 4 Semi skimmed cow milk 200 ml Extracellular 40 mg protein Vesicles particles 1 Field, Lönnerdal, Admyre, et al., Hata, et al., 2010
6 EVs are phospholipid bilayer vesicles Giuseppina Turturici et al. Am J Physiol Cell Physiol 2014;306:C621-C633
7 EVs in intercellular communication Secreting cell srna Cytosolic and membrane proteins Recipient cell Regulation of the Immune system
8 Milk EVs contain mirnas Olivieri et al. Immunity & Ageing :11
9 The hypothesis Cow milk-derived EVs modulate the (mucosal) immune system and thereby affect disease in RA patients
10 Isolation protocol milk EVs Skimmed milk 3,000g, 15 mins (3-4x) Defatted milk 12,000g, 60 min 35,000g, 60 min 70,000g, 60 min 0.2μm filtration Adapted protocol for exosome isolation from bovine milk 1 Milk Supernatant Extracellular vesicles 1 Yamada, et al., 2012 ExoQuick Overnight or 100,000g Analysis: NanoSight NTA mrna detection mirna detection
11 Intensity (%) Characterization of cow milk EVs Particle size Tetraspanin EM EM CD nm NTA Capture + NTA Diameter [nm]
12 RNA characterization of cow milk EVs mrna content EVs mirna content EVs Mammary gland cells Somatic cells
13 Protein profiling of cow milk EVs 1D-LC-MS/MS identified 64 proteins 1. Transmembrane proteins CD36, CD59, CD81 2. Cytosolic proteins Rab-1b, Rab-11a 3. Intracellular structural proteins actin, myosin-xix 4. Precursor of milk proteins casein, α-lactalbumin, LG, osteopontin
14 Stability of milk EVs Milk EVs NanoSight Particle Tracking RAW EVs NF B-Luciferase reporter assay Treatment Condition Duration Acidification ph 2,0 30 mins Heat (boiling) 105 C 30 mins Freeze-thawing Liquid NO 2 3 times RAW cell line containing a NFkBluciferase construct
15 Convocal microscopy Cellular uptake of PKH-68 labelled EVs RAW Flow cytometry RAW 264.7
16 EV uptake by murine intestinal explants CCD Isolation murine small intestine 2. Cleaning and stitching bottom 3. PKH-67 labeled EVs 4. 24h incubation at 37 C 5. Extensive rinsing 6. Imaging (CCD camera) Small intestinal tissue explant IVIS analysis
17 Cow milk-derived EVs: Diameter around 100 nm All have the characteristics of genuine exosomes Possess mirnas and mrnas (e.g milk specific proteins) Remain intact under harsh conditions Are taken up by numerous different cell types BUT ARE THEY FUNCTIONAL?
18 Milk EVs posses active TGF- (CAGA)12-Luciferase reporter in NIH-3T3 fibroblasts
19 T-cell immunity in RA patients IL-2 TGF IL-10 Treg Foxp3 Tolerance CD4 + Th TGF CD25 1, 2 TGF IL-6 Th17 ROR T IL-17 A/F IL-6 TNF IL-22 Inflammation (autoimmunity) 1 Betteli, et al., Mangan, et al., 2006
20 Milk EVs induce Th17 differentiation EVs also enhance IL-22 expression, but neither IL-21, TGF nor FoxP3
21 Milk EVs also induce Tregs in vitro Differentiation into Th17 and Tregs induced by milk Evs is TGF- mediated
22 Functional properties of milk EVS: Are able to activate a TGF -specific reporter bioassay Can mediate differentiation of naive T-cells into both Th17 or regulatory T-cells This T-cell differentiation effect by EVs is partially mediated by TGF- WHAT WILL BE THE EFFECT OF ORALLY APPLIED COW MILK EVs ON ARTHRITIS?
23 1 st model: IL-1 receptor antagonist KO mice MILK EVs Daily oral administration of EVs start at week 5 of age. High dose = 1200 µg EVs / mouse Low dose = 171 µg EVs / mouse
24 Disease Incidence (%) Ankle joint Macroscopic score (0-4) Ankle Joint Microscroscopic score(0-3) Results IL-1Ra arthritis model A B C PBS Milk (Low) Milk (High) PBS Milk (Low) Milk (high) 2.0 PBS Milk (Low) Milk (high) * * Weeks after treatment D Week after treatment 0.0 Infiltrate Exudate Cartilage depletion Bone Marrow Cellularity PBS Milk (low) Milk (high)
25 2 nd model: Collagen-induced arthritis Macroscopic score (paw 0-2) 2 Ad.CMV-Luc Immunization i.d. bovine CII/CFA Booster i.p. CII/PBS 1,5 1 0,5 Normal paw day -7 day 0 day 7 day 14 day 21 0 day 23 day 25 day 27 day 29 day 31 day 33 day 35 Mildly affected Full expression MILK EVs Administration of EVs via drinking water High dose = 115 µg EVs/ml 400 µg EVs/mouse Low dose = 38 µg EVs/ml 140 µg EVs/mouse
26 Disease Incidence (%) Ankle Joint M acroscoscopic score (0-8) Ankle Joint Microscopic score (0-3) A D PBS Milk (low) Milk (high) Days after immunization Results CIA model B PBS Milk (low) Milk (High) * * Days after immunization * * * * C Infiltrate PBS Milk (low) Milk (High) Exudate Cartilage depletion Histological score of only the affected mice * Cartilage erosion * Bone Marrow Cellularity PBS Milk (low) Milk (high)
27 Adherent splenocytes TNF- (pg/ml) Adherent splenocytes M CP-1 (pg/ml) Effect of milk EVs on innate immunity TNF MCP ** * Milk EVs 0 g/ml 20 g/ml 200 g/ml * *** *** *** *** ** hours 48 hours 72 hours 0 24 hours 48 hours 72 hours LPS stimulation LPS stimulation Isolated adherent murine splenocytes were incubated 24, 48, and 72 h with milk EVs (20, 200 μg/ml) and thereafter stimulated with LPS (10 ng/ml) for 6 h, and supernatants used in Luminex.
28 APC mrna relative expression (2 - CT ) Serum (pg/ml) Effect of milk EVs on innate immunity IN VIVO IL-1RA KO MICE IN VIVO CIA MICE 1.5 PBS Milk (low) Milk (High) 1500 PBS Milk (low) 1000 Milk (high) ** * IL-6 KC MCP-1 0 MCP-1 IL-6
29 Total IgG Absorbance (450nm) IgG1 Absorbance (450nm) IgG2a Absorbance (450nm) Milk EVs decrease the adaptive immunity in CIA mice * PBS Milk (low) 0.0 Milk (high) Dilution * Th2 0.1 PBS Milk (low) 0.0 Milk (high) Dilution * 0.2 PBS Milk (low) 0.0 Milk (High) Dilution * Th1
30 M ixed Splenocytes mrna relative expression (2 - CT ) Milk EVs decrease the adaptive immunity in CIA mice PBS Milk (low) Milk (High) *** *** *** ** T-bet GATA3 FOXP3 RORyT Th1 Th2 Treg Th17
31 Therapeutic potential of milk EVs: Oral delivery (prophylactic) delays onset of disease in two models of rheumatoid arthritis Diminishes cartilage pathology and bone marrow inflammation Reduces the innate cytokine response to LPS (TLR4 signaling) Evidence for reduced Th1 (Tbet, IgG2a) and Th17 levels in mice
32 Can cow milk EVs be used to treat RA? Cow milk EVs are bioactive: anti-inflammatory immunoregulatory Oral uptake of cow milk EVs ameliorate disease in 2 RA models. New questions emerge: Is complete milk different from their EVs? Is raw milk different from processed? Are milk EVs a heterogenous group? What and where is the mode of action? Can other diseases benefit from cow milk EVs?
33 Part II. Beneficial effect of milk on osteoporosis is debatable Role of EVs?
34 Acknowledgements Radboudumc Experimental Rheumatology: Onno Arntz Bartijn Pieters Miranda Bennink Marina Chaves de Oliveira Silke Beermann Mathijs Broeren Marieke de Vries Claire Waterborg Department of Molecular Materials Daniela Wilson Zaskia Eksteen-Akeroyd Radboud proteomics center Jolein Gloerich Food Chemistry lab, Wageningen Peter Wierenga N o ). Grant number
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