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