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Transcript of Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site...
Role of inflammation in the pathogenesis of age-related comorbidities
Jacqueline CapeauJacqueline Capeau
INSERM U938, Université Pierre et Marie Curie INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Faculté de Médecine, site Saint-Antoine,
Hôpital Tenon, Paris, France Hôpital Tenon, Paris, France
Acute inflammation
« Rubor et tumor cum calore et dolore » Redness and swelling with heat and painCorneluis Celsius 1rst century AD
R Medzhitov Cell 2010
Inflammation pathways components
Infection
InjuryInflammationInflammation
Host defense
Tissue repair
Inflammation and the stress response
R Medzhitov Cell 2010
A Freund Trends Molecular Med 2010
Chronic low-grade inflammation is associated with most age-related diseases
Hs-CRP< 10mg/lHs-IL6Hs-CRP< 10mg/lHs-IL6
Chronic low-grade inflammation
XNot caused by classic inducers: infection and injuryDue to tissue stress and malfunction?Not caused by classic inducers: infection and injuryDue to tissue stress and malfunction?
HY Chung Aging Research Reviews 2008,9;8:18 HY Chung Aging Research Reviews 2008,9;8:18
« Inflammaging »« Inflammaging »« Immune activation »Proinflammatory cytokines produced by immune cells: monocytes/macrophages and T lymphocytes but also endothelial cells, adipocytes, epithelial cells
Implication of inflammation in aging processes
Salminen Cell Signal 2010
Gut-derived inflammation and metabolic risk
Gut-derived inflammation and metabolic risk
1014 bacteria and archaeaLarge diversity: 1100species
150 more gene than our own genome
From Burcelin London 2010
Intestinal Microbiota
M Serino Diabetes Metab 2009
Role of food composition in systemic inflammation and metabolic consequences
sCD14sCD14
From VD Dixit J Leukoc Biol 2008
Role of adipose tissue in inflammagingGUT
LPS, sCD14
Inflammation, immune activation And cardio-vascular risk
Inflammation, immune activation And cardio-vascular risk
AM LundbergClinicalImmunology 2010
Initiation of atherosclerosis : activation of macrophages
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
Role of immune activation in plaque inflammation and risk of rupture and thrombosis
J Andersson ClinicalImmunology 2010
Increased levels of CRP and LDL-c decrease the probability of cardiovascular event-free survival
EY Yang J Am Coll Cardiology 2009EY Yang J Am Coll Cardiology 2009
Role of personal and life-style factorsRole of personal and life-style factors
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 agingPremature aging
AGE
INCI
DEN
CE
10-15 years10-15 years
HIV+HIV+ HIV-HIV-
Non-AIDS defining comorbidities
From J CampisiFrom J Campisi
25J Neuhaus CID 2010J 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 age Participants 45-76 years of age
Biomarker No. Median level [IQR] % Diff. (P) No. Median level
[IQR] % Diff. (P)
hsCRP, g/mL 140 2.13 (0.77-5.20) 40.2 (<.001) 293 2.83 (1.07-6.80) 37.8 (<.001)
IL-6, pg/mL 139 1.89 (1.15-3.42) 39.0 (<.001) 291 2.64 (1.55-4.14) 60.1 (<.001)
D-dimer, g/mL 140 0.21 (0.15-0.46) NA 293 0.29 (0.17-0.57) 49.1 (<.001)
Cystatin C, mg/dL 86 0.90 (0.78-0.97) NA 130 1.00 (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.
AGE
INCI
DEN
CE
10-15 years10-15 years
HIV+HIV+ HIV-HIV-
Why ?
From J CampisiFrom J Campisi
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 agingEarly aging
Virus
Immunity ART
Inflammaging in HIV-infected patients
Virus and inflammationVirus and inflammation
The level of IL-6 is related to viral load in HIV-infected patients with a controlled VL
-10
10
30
50
70
90
110
130
150
IL6 <0.685 IL6 >0.685
CV c
opie
s/m
L
p=0.0408
CRPUS <1 CRPUS: 1-3 CRPUS >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
ART and inflammationART and inflammation
C Lagathu Antiviral Ther 2007
Effect of different antiretrovirals on human adipocytes : PI and NRTI
Some PI induce oxidative stress and inflammation in endothelial cells:
Beneficial effect of statins
Lefèvre ATVB 2010
Chronic immune activation and inflammationHIV Infection
and replication
HIV Infection and
replication
Immune activation: Acquired and Innate Immunity
Immune activation: Acquired and Innate Immunity
Immune depletion and immune senescenceImmune depletion and immune senescence
Anti-HIV immunityAnti-HIV immunity Intestinal bacterial translocationIntestinal bacterial translocation
Reactivation of other virusesReactivation of other viruses
Lymphocytes T Differentiation and senescenceLymphocytes T Differentiation and senescence Proinflammatory cytokines secretionProinflammatory cytokines secretion
D’après V Appay J Pathol 2008Non-AIDS defining morbidity and mortalityNon-AIDS defining morbidity and mortality
Production of viral proteinsProduction of viral proteins
Chronic inflammationChronic inflammation
Bacterial translocation in naïve and treated patients Bacterial translocation in naïve and treated patients
LPS, 16S rDNA LPS, 16S rDNA
sCD14, innate immunity activation sCD14, innate immunity activation
acquired immunity activation, CD4, CD8 acquired immunity activation, CD4, CD8
immune depletion/senescence immune depletion/senescence
JM Brenchley Nat Med 2006JM Brenchley Nat Med 2006
R Rajasuriar JID 2010W Jiang JID 2009W Jiang JID 2009
IL-6 IL-6
CRP CRP
Relations between bacterial translocation, immune activation and chronic inflammation
Role of immune activation and inflammation in non-AIDS-defining mortality
Role of immune activation and inflammation in non-AIDS-defining mortality
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
NG Sandler CID 2011
Bacterial translocation naïve and treated patients Bacterial translocation naïve and treated patients
LPS, 16S rDNA LPS, 16S rDNA
sCD14, innate immunity activation sCD14, innate immunity activation
acquired immunity activation, CD4, CD8 acquired immunity activation, CD4, CD8
immune depletion/senescence immune depletion/senescence
JM Brenchley Nat Med 2006JM Brenchley Nat Med 2006
R Rajasuriar JID 2010W Jiang JID 2009W Jiang JID 2009
IL-6 IL-6
CRP CRP
Relations between bacterial translocation, immune activation and cardio-vascular risk
Cardio-vascular riskCardio-vascular riskRC Kaplan Atherosclerosis, CID 2011
RC Kaplan CID 2011
IMT is associated with CRP and insulin resistance
AC Ross CID 2009AC Ross CID 2009
Role of bacterial translocation and immune activation
In neurocognitive disorders
Role of bacterial translocation and immune activation
In neurocognitive disorders
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
Plasma LPS increased even in mild forms of impairment, whether symptomatic or not
J Lyons CROI 2011 # 405
Lipodystrophy worsen inflammatory state and metabolic disorders
Lipodystrophy worsen inflammatory state and metabolic disorders
Lipodystrophic HIV-infected patients have increased CRP and decreased adiponectin levels
K Samaras Obesity 2009K Samaras Obesity 2009
Lipodystrophy and ART predict atherosclerosis lesions in HIV-infected patients
G Guaraldi Atherosclerosis 2010
OR Confidence interval P-value
Male sex 2.8 1.3-6.1 0.009
Age per 1 year 1.12 1.07-1.17 <0.001
BMI 1.09 0.98-1.21 NS
Chol T 0.99 0.99-1.01 NS
HDL C 1.00 0.98-1.03 NS
Hypertension 2.09 1.13-3.88 0.018
Exposure to ART, per 1 y 1.21 1.07-1.37 0.002
No lipodystrophy 1 ref
Lipoatrophy 3.82 1.11-13.1 0.033
Lipohypertrophy 7.65 1.71-37.17 0.008
Mixed form 4.36 1.26-15.01 0.02
Multivariable logistic analysis for independent predictors of coronary artery calcium
The inflammatory status 48 weeks after cART initiation is associated with an increased
incidence of diabetes
TT Brown Diabetes Care 2010
TT Brown Diabetes Care 2010
TL Stanley AIDS 2011
TL Stanley AIDS 2011
R Scherzer AIDS 2011
Increased visceral adipose tissue is associated with increased 5-year mortality
in the FRAM study
What to do ?What to do ?
JID 2011
Statins to decrease immune activation?
VIHSTATINE: effect of statins 45 days (pravastatine and rosuvastatine) on CRP levels
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 2011E Aslangul AIDS 2011
Statins to decrease systemic inflammation
Chronic immune activation and inflammationHIV Infection
and replication
HIV Infection and
replication
Immune activation: Acquired and Innate Immunity
Immune activation: Acquired and Innate Immunity
Immune depletion and immune senescenceImmune depletion and immune senescence
D’après V Appay J Pathol 2008
Non-AIDS defining morbidity and mortalityNon-AIDS defining morbidity and mortality
Chronic inflammationChronic inflammation
TreatmentTreatmentAgeAge Personal factorsPersonal factorsLipodystrophyLipodystrophy
Involved in progeriaInvolved in progeria
11-year children
Other syndromes of premature aging linked to defects in the enzyme that maturates prelamin A to lamin AOther syndromes of premature aging linked to defects in the enzyme that maturates prelamin A to lamin A
Prelamin APrelamin A : a senescence protein : a senescence protein
From Liu, Nature Medicine 2005
Accumulation of farnesylated prelamin A Accumulation of farnesylated prelamin A results in accelerated agingresults in accelerated aging
Prelamin A a biomarker of vascular aging in human subjects
Prelamin A a biomarker of vascular aging in human subjects
CD Ragnauth Circulation 2010CD Ragnauth Circulation 2010
Aged vascular smooth muscle cells accumulate prelamin A and exhibit nuclear morphology defects and senescence markersAged vascular smooth muscle cells accumulate prelamin A and exhibit nuclear morphology defects and senescence markers
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)Some PIs inhibit ZMPSTE24 and lead to prelamin A accumulation (M Caron AIDS 2003, M Caron Cell Death Diff 2007, C Coffinier PNAS 2007)
PBMC from HIV-infected patients under PI/r express prelamin A and senescence markers
HIV+ patients under HIV+ patients under NRTI without PINRTI without PI
HIV+ patients HIV+ patients under PI/runder PI/r
C Navarro Hum Mol Gen 2006
The process of prelamin A maturation into lamin A: effect of statins and farnesyl-transferase inhibitors (FTI)
statinstatin
FTIFTI
Decreased expression of senescence markers in PBMC from HIV-infected patients under PI/r and a statin
Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells
DrugsDrugs
Inhibition of ZMP-STE24Inhibition of ZMP-STE24
Accumulation of farnesylated prelamin AAccumulation of farnesylated prelamin A
Increased ROSIncreased ROS
Activation of NFkBActivation of NFkB
Increased IL6, IL8, MCP-1Increased IL6, IL8, MCP-1 Systemic low grade inflammationSystemic low grade inflammation
Cellular senescenceCellular senescence
Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells: beneficial effect of statins
DrugsDrugs
Inhibition of ZMP-STE24Inhibition of ZMP-STE24
Accumulation of farnesylated prelamin AAccumulation of farnesylated prelamin A
Increased ROSIncreased ROS
Activation of NFkBActivation of NFkB
Increased IL6, IL8, MCP-1Increased IL6, IL8, MCP-1 Systemic low grade inflammationSystemic low grade inflammation
Cellular senescenceCellular senescence
StatinsStatins
Accelerated aging model in HIV infectionrole of immune activation/senescence
S Desai and A Landay Curr HIV/AIDS Res 2010
Neurodegenerative diseases , immune activation and inflammation
Neurodegenerative diseases , immune activation and inflammation
S Amor Immunology 2010
Inflammation and activation of stress signals induces insulin resistance
G Hotamisligil Cell 2010
NFBNFB
Inflammation and agingInflammation and aging
Acute inflammation
RednessSwellingHeatPain
Local Resolutive
Chronic low-grade inflammation, « inflammaging »
Low-gradeControlled AsymptomaticChronicSystemic
cytokines (IL6, IL8) and coagulation factorsSubclinical infection with common viruses (CMV)Genetic components ROS
adaptative immunity« released » innate immunity: increased pro-inflammatory responses
Frailty, age-related diseasesGiunta B J Neuroinflammation, 2008
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, ObesityM Serino Diabetes Metab 2009
J Lyons CROI 2011 # 405