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Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France Role of inflammation.

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Presentation on theme: "Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France Role of inflammation."— Presentation transcript:

1 Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France Role of inflammation in the pathogenesis of age- related comorbidities Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France

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3 Acute inflammation « Rubor et tumor cum calore et dolore » Redness and swelling with heat and pain Corneluis Celsius 1rst century AD

4 R Medzhitov Cell 2010 Inflammation pathways components Infection Injury Inflammation Host defense Tissue repair

5 Inflammation and the stress response R Medzhitov Cell 2010

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7 A Freund Trends Molecular Med 2010 Chronic low-grade inflammation is associated with most age-related diseases Hs-CRP< 10mg/l Hs-IL6 Hs-CRP< 10mg/l Hs-IL6

8 Chronic low-grade inflammation X Not caused by classic inducers: infection and injury Due to tissue stress and malfunction? Not caused by classic inducers: infection and injury Due to tissue stress and malfunction?

9 HY Chung Aging Research Reviews 2008,9;8:18 « Inflammaging » « Immune activation » Proinflammatory cytokines produced by immune cells: monocytes/macrophages and T lymphocytes but also endothelial cells, adipocytes, epithelial cells

10 Implication of inflammation in aging processes Salminen Cell Signal 2010

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12 Gut-derived inflammation and metabolic risk Gut-derived inflammation and metabolic risk

13 10 14 bacteria and archaea Large diversity: 1100species 150 more gene than our own genome From Burcelin London 2010 Intestinal Microbiota

14 M Serino Diabetes Metab 2009 Role of food composition in systemic inflammation and metabolic consequences sCD14

15 From VD Dixit J Leukoc Biol 2008 Role of adipose tissue in inflammaging GUT LPS, sCD14

16 Inflammation, immune activation And cardio-vascular risk Inflammation, immune activation And cardio-vascular risk

17 AM LundbergClinicalImmunology 2010 Initiation of atherosclerosis : activation of macrophages

18 AM LundbergClinicalImmunology2010 TLR stimulation of macrophages results in the release of proinflammatory cytokines, TNF, IL-1 and IL-6, that can have both local and systemic effects. Role of innate and acquired immunity in atherosclerosis progression

19 Role of immune activation in plaque inflammation and risk of rupture and thrombosis J Andersson ClinicalImmunology 2010

20 Increased levels of CRP and LDL-c decrease the probability of cardiovascular event-free survival EY Yang J Am Coll Cardiology 2009

21 Role of personal and life-style factors

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23 Early occurrence of age-related comorbidities Osteoporosis Neurocognitive dysfunction Sarcopenia Frailty Cardio-vascular risk and hypertension Fat redistribution and lipodystrophy Insulin resistance, diabetes et dyslipidemia Non-AIDS related Cancers HIV-infected patients Premature aging

24 AGE INCIDENCE 10-15 years HIV+ HIV- Non-AIDS defining comorbidities From J Campisi

25 25 J Neuhaus CID 2010 Increased levels of proinflammatory and prothrombotic markers in HIV-infected patients as compared to the general population Biomarkers Levels in SMART Study Participants Receiving Antiretroviral Therapy (ART) Who Had an HIV RNA Level 400 Copies/mL and Percentage Differences in Levels Versus CARDIA and MESA Study Participants Participants 33-44 years of ageParticipants 45-76 years of age BiomarkerNo. Median level [IQR] % Diff. (P)No. Median level [IQR] % Diff. (P) hsCRP, g/mL 1402.13 (0.77-5.20)40.2 (<.001)2932.83 (1.07-6.80)37.8 (<.001) IL-6, pg/mL 1391.89 (1.15-3.42)39.0 (<.001)2912.64 (1.55-4.14)60.1 (<.001) D-dimer, g/mL 1400.21 (0.15-0.46)NA2930.29 (0.17-0.57)49.1 (<.001) Cystatin C, mg/dL 860.90 (0.78-0.97)NA1301.00 (0.86-1.16)20.9 (<.001) Data are the median level and (interquartile range [IQR]). CARDIA, Coronary Artery Development in Young Adults; Diff., difference; MESA, Multi-Ethnic Study of Atherosclerosis; NA, not available; SMART, Strategies for Management of Anti-Retroviral Therapy.

26 AGE INCIDENCE 10-15 years HIV+ HIV- Why ? From J Campisi

27 Role of chronic infection Role of treatment Role of inflammation/immune activation Role of immune deficiency/senescence Role des personal factors : age, tobacco, coinfections Early aging Virus Immunity ART Inflammaging in HIV-infected patients

28 Virus and inflammation

29 The level of IL-6 is related to viral load in HIV-infected patients with a controlled VL IL6 <0.685IL6 >0.685 CV copies/mL p=0.0408 CRPUS <1CRPUS: 1-3CRPUS >3 p=ns 122 patients, ART-treated, VL: 1 to 500 copies/ml, IL-6 values were positively related to HIV-RNA levels (rho=0.217 p=0.017) JP Bastard Workshop Adverse Drug ReactionComorbidities London 2010

30 ART and inflammation

31 C Lagathu Antiviral Ther 2007 Effect of different antiretrovirals on human adipocytes : PI and NRTI

32 Some PI induce oxidative stress and inflammation in endothelial cells: Beneficial effect of statins Lefèvre ATVB 2010

33 Chronic immune activation and inflammation HIV Infection and replication Immune activation: Acquired and Innate Immunity Immune depletion and immune senescence Anti-HIV immunity Intestinal bacterial translocation Reactivation of other viruses Lymphocytes T Differentiation and senescence Proinflammatory cytokines secretion Daprès V Appay J Pathol 2008 Non-AIDS defining morbidity and mortality Production of viral proteins Chronic inflammation

34 Bacterial translocation in naïve and treated patients LPS, 16S rDNA sCD14, innate immunity activation acquired immunity activation, CD4, CD8 immune depletion/senescence JM Brenchley Nat Med 2006 R Rajasuriar JID 2010 W Jiang JID 2009 IL-6 CRP Relations between bacterial translocation, immune activation and chronic inflammation

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36 Role of immune activation and inflammation in non-AIDS-defining mortality

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38 Fibrinogen and CRP are independent risk factors for mortality in the FRAM study Even in patients with preserved CD4 count >500 cells per microliter, inflammation remains an important factor for mortality P Tien JAIDS 2010

39 NG Sandler CID 2011

40 Bacterial translocation naïve and treated patients LPS, 16S rDNA sCD14, innate immunity activation acquired immunity activation, CD4, CD8 immune depletion/senescence JM Brenchley Nat Med 2006 R Rajasuriar JID 2010 W Jiang JID 2009 IL-6 CRP Relations between bacterial translocation, immune activation and cardio-vascular risk Cardio-vascular risk RC Kaplan Atherosclerosis, CID 2011

41 RC Kaplan CID 2011

42 IMT is associated with CRP and insulin resistance AC Ross CID 2009

43 Role of bacterial translocation and immune activation In neurocognitive disorders Role of bacterial translocation and immune activation In neurocognitive disorders

44 179 subjects, median age 48 years, 14 (8%) patients with neuropsychological deficit (ND), 22 (12%) with asymptomatic neurocognitive impairment (ANI), 14 (8%) with mild cognitive impairment (MCD), and 5 (3%) with HIV-associated dementia (HAD) : 31% affected. Mean LPS values for NT were 94±47 pg/mL, ND: 131±37 pg/mL, ANI: 122±61 pg/mL, MCD: 131±8 pg/mL, HAD: 129±45 pg/mL (p = 0.002). In multivariate analysis, plasma LPS >120 pg/mL (p = 0.0001) and pDNA (p = 0.032) were independent risk factors for NI. H Carsenti-Dellamonica CROI 404 Plasma LPS increased even in mild forms of impairment, whether symptomatic or not

45 J Lyons CROI 2011 # 405

46 Lipodystrophy worsen inflammatory state and metabolic disorders

47 Lipodystrophic HIV-infected patients have increased CRP and decreased adiponectin levels K Samaras Obesity 2009

48 Lipodystrophy and ART predict atherosclerosis lesions in HIV-infected patients G Guaraldi Atherosclerosis 2010 ORConfidence intervalP-value Male sex2.81.3-6.10.009 Age per 1 year1.121.07-1.17<0.001 BMI1.090.98-1.21NS Chol T0.990.99-1.01NS HDL C1.000.98-1.03NS Hypertension2.091.13-3.880.018 Exposure to ART, per 1 y1.211.07-1.370.002 No lipodystrophy1 ref Lipoatrophy3.821.11-13.10.033 Lipohypertrophy7.651.71-37.170.008 Mixed form4.361.26-15.010.02 Multivariable logistic analysis for independent predictors of coronary artery calcium

49 The inflammatory status 48 weeks after cART initiation is associated with an increased incidence of diabetes TT Brown Diabetes Care 2010

50 TL Stanley AIDS 2011

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52 R Scherzer AIDS 2011 Increased visceral adipose tissue is associated with increased 5-year mortality in the FRAM study

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54 What to do ?

55 JID 2011 Statins to decrease immune activation?

56 VIHSTATINE: effect of statins 45 days (pravastatine and rosuvastatine) on CRP levels After 45 days of statin therapy the median change in the hsCRP concentration was -20% overall (-0.6 mg/l, p<0.001) respectively -22% and -16% in the pravastatin and rosuvastatin groups (p = 0.932). The LDL-c level fell by a median of 19% in the pravastatin group and 37% in the rosuvastatin group (P < 0.001 for both) The triglyceride levels fell by respectively 3% and 26% (p = 0.008 for both) There was no correlation between the change in the hsCRP level and changes in the markers of lipid, endothelial and inflammatory status E Aslangul AIDS 2011 Statins to decrease systemic inflammation

57 Chronic immune activation and inflammation HIV Infection and replication Immune activation: Acquired and Innate Immunity Immune depletion and immune senescence Daprès V Appay J Pathol 2008 Non-AIDS defining morbidity and mortality Chronic inflammation Treatment Age Personal factors Lipodystrophy

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59 Involved in progeria 11-year children Other syndromes of premature aging linked to defects in the enzyme that maturates prelamin A to lamin A Prelamin A : a senescence protein

60 From Liu, Nature Medicine 2005 Accumulation of farnesylated prelamin A results in accelerated aging

61 Prelamin A a biomarker of vascular aging in human subjects CD Ragnauth Circulation 2010 Aged vascular smooth muscle cells accumulate prelamin A and exhibit nuclear morphology defects and senescence markers

62 Some PIs induce prelamin A accumulation and cellular senescence in endothelial cells C Lefèvre ATVB, 2010 IL-6 secretion Some PIs inhibit ZMPSTE24 and lead to prelamin A accumulation (M Caron AIDS 2003, M Caron Cell Death Diff 2007, C Coffinier PNAS 2007)

63 PBMC from HIV-infected patients under PI/r express prelamin A and senescence markers HIV+ patients under NRTI without PI HIV+ patients under PI/r

64 C Navarro Hum Mol Gen 2006 The process of prelamin A maturation into lamin A: effect of statins and farnesyl-transferase inhibitors (FTI) statin FTI

65 Decreased expression of senescence markers in PBMC from HIV-infected patients under PI/r and a statin

66 Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells Drugs Inhibition of ZMP-STE24 Accumulation of farnesylated prelamin A Increased ROS Activation of NFkB Increased IL6, IL8, MCP-1 Systemic low grade inflammation Cellular senescence

67 Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells: beneficial effect of statins Drugs Inhibition of ZMP-STE24 Accumulation of farnesylated prelamin A Increased ROS Activation of NFkB Increased IL6, IL8, MCP-1 Systemic low grade inflammation Cellular senescence Statins

68 Accelerated aging model in HIV infection role of immune activation/senescence S Desai and A Landay Curr HIV/AIDS Res 2010

69 Neurodegenerative diseases, immune activation and inflammation S Amor Immunology 2010

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71 Inflammation and activation of stress signals induces insulin resistance G Hotamisligil Cell 2010 NF B

72 Inflammation and aging Acute inflammation Redness Swelling Heat Pain Local Resolutive Chronic low-grade inflammation, « inflammaging » Low-grade Controlled Asymptomatic Chronic Systemic cytokines (IL6, IL8) and coagulation factors Subclinical infection with common viruses (CMV) Genetic components ROS adaptative immunity « released » innate immunity: increased pro- inflammatory responses Frailty, age-related diseases Giunta B J Neuroinflammation, 2008

73 High-fat food, antibiotics, dietary fibers (prebiotics) and bacterial additives (probiotics) can change the intestinal microflora ecology, leading to an unbalanced Firmicutes –Bacteroidetes ratio. Diabetes, Obesity M Serino Diabetes Metab 2009

74 J Lyons CROI 2011 # 405


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