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Role of inflammation in the pathogenesis of agerelated comorbidities
Jacqueline Capeau
INSERM U938, Université Pierre et Marie Curie
Faculté de Médecine, site Saint-Antoine,
Hôpital Tenon, Paris, France
1. Inflammation
1. Chronic inflammation and aging
1. Why?
1. Inflammation, immune activation and HIV infection
2. Consequences on morbidity/mortality in HIVinfected patients
3. Anti-inflammatory treatment: Statins?
Acute inflammation
« Rubor et tumor cum calore et dolore »
Redness and swelling with heat and pain
Corneluis Celsius 1rst century AD
Inflammation pathways components
Infection
Injury
R Medzhitov Cell 2010
Host defense
Inflammation
Tissue repair
Inflammation and the stress response
R Medzhitov Cell 2010
1. Inflammation
1. Chronic inflammation and aging
1. Why?
2. Inflammation, immune activation and HIV infection
3. Consequences on morbidity/mortality in HIVinfected patients
4. Anti-inflammatory treatment: Statins?
Chronic low-grade inflammation is associated
with most age-related diseases
Hs-CRP< 10mg/l
Hs-IL6
A Freund Trends Molecular Med 2010
Chronic low-grade inflammation
Not caused by classic inducers: infection and injury
Due to tissue stress and malfunction?
« Inflammaging »
HY Chung Aging Research Reviews 2008,9;8:18
« 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
1. Inflammation
1. Chronic inflammation and aging
1. Why?
2. Inflammation, immune activation and HIV infection
3. Consequences on morbidity/mortality in HIVinfected patients
4. Anti-inflammatory treatment: Statins?
Gut-derived inflammation
and metabolic risk
Intestinal Microbiota
1014 bacteria and archaea
Large diversity: 1100species
150 more gene than our
own genome
From Burcelin London 2010
Role of food composition in systemic
inflammation and metabolic consequences
sCD14
M Serino Diabetes Metab 2009
Role of adipose tissue in inflammaging
GUT
LPS, sCD14
From VD Dixit J Leukoc Biol 2008
Inflammation, immune activation
And cardio-vascular risk
Initiation of atherosclerosis : activation of
macrophages
AM LundbergClinicalImmunology 2010
Role of innate and acquired immunity in
atherosclerosis progression
TLR stimulation of macrophages results in the release of proinflammatory cytokines,
TNFa, IL-1 and IL-6, that can have both local and systemic effects.
AM LundbergClinicalImmunology2010
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 2009
Role of personal and life-style factors
1. Inflammation
1. Chronic inflammation and aging
1. Why?
2. Inflammation, immune activation and HIV
infection
3. Consequences on morbidity/mortality in HIVinfected patients
4. Anti-inflammatory treatment: Statins?
HIV-infected patients
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
Premature aging
Non-AIDS defining comorbidities
HIV-
INCIDENCE
HIV+
10-15 years
AGE
From J Campisi
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
Median level
[IQR]
No.
Median level
[IQR]
Biomarker
No.
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)
86 0.90 (0.78-0.97)
NA
130 1.00 (0.86-1.16) 20.9 (<.001)
Cystatin C, mg/dL
% Diff. (P)
Participants 45-76 years of age
% Diff. (P)
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.
25
J Neuhaus CID 2010
Why ?
INCIDENCE
HIV+
HIV-
Inflammation, Immune
Activation,
thrombotic risk
HIV, ART
Immune
depletion/senescence
10-15 years AGE
From J Campisi
Inflammaging in HIV-infected patients
 Role of chronic infection
 Role of treatment
 Role of inflammation/immune activation
 Role of immune deficiency/senescence
 Role des personal factors : age, tobacco, coinfections
Virus
Early aging
Immunity
ART
Virus and inflammation
The level of IL-6 is related to viral load in
HIV-infected patients with a controlled VL
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)
150
130
110
p=0.0408
p=ns
CV copies/mL
90
70
50
30
10
-10
IL6 <0.685
IL6 >0.685
CRPUS <1
CRPUS: 1-3 CRPUS >3
JP Bastard Workshop Adverse Drug ReactionComorbidities London 2010
ART and inflammation
Effect of
different
antiretrovirals
on human
adipocytes :
PI and NRTI
C Lagathu Antiviral
Ther 2007
Some PI induce oxidative stress and
inflammation in endothelial cells:
Beneficial effect of statins
Lefèvre ATVB 2010
Chronic immune activation and inflammation
HIV Infection
and replication
Anti-HIV immunity
Production of viral
proteins
Intestinal bacterial
translocation
Reactivation of
other viruses
Immune activation: Acquired and Innate Immunity
Lymphocytes T Differentiation and senescence
Proinflammatory cytokines secretion
Chronic inflammation
Immune depletion and immune senescence
Non-AIDS defining morbidity and mortality
D’après V Appay J Pathol 2008
Relations between bacterial translocation,
immune activation and chronic inflammation
 Bacterial translocation in naïve and treated patients
 LPS, 16S rDNA
 sCD14, innate immunity activation
 IL-6
 acquired immunity activation, CD4, CD8
 CRP
 immune depletion/senescence
JM Brenchley Nat Med 2006
W Jiang JID 2009
R Rajasuriar JID 2010
1. Inflammation
1. Chronic inflammation and aging
1. Why?
2. Inflammation, immune activation and HIV infection
3. Consequences on morbidity/mortality in HIVinfected patients
4. Anti-inflammatory treatment: Statins?
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
Relations between bacterial translocation,
immune activation and cardio-vascular risk
 Bacterial translocation naïve and treated patients
 LPS, 16S rDNA
 sCD14, innate immunity activation
 IL-6
 acquired immunity activation, CD4, CD8
 CRP
 immune depletion/senescence
JM Brenchley Nat Med 2006
W Jiang JID 2009
R Rajasuriar JID 2010
RC Kaplan Atherosclerosis, CID 2011
Cardio-vascular risk
RC Kaplan CID 2011
IMT is associated with CRP and insulin
resistance
AC Ross CID 2009
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.
Plasma LPS increased even in mild forms of impairment,
whether symptomatic or not
H Carsenti-Dellamonica CROI 404
J Lyons CROI 2011 # 405
Lipodystrophy worsen inflammatory state and
metabolic disorders
Lipodystrophic HIV-infected patients have
increased CRP and decreased adiponectin levels
K Samaras Obesity 2009
Lipodystrophy and ART predict atherosclerosis
lesions in HIV-infected patients
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
G Guaraldi Atherosclerosis 2010
The inflammatory status 48 weeks after cART
initiation is associated with an increased
incidence of diabetes
TT Brown
Diabetes Care
2010
TL Stanley AIDS 2011
TL Stanley AIDS 2011
Increased visceral adipose tissue is associated
with increased 5-year mortality
in the FRAM study
R Scherzer AIDS 2011
1. Inflammation
1. Chronic inflammation and aging
1. Why?
2. Inflammation, immune activation and HIV infection
3. Consequences on morbidity/mortality in HIVinfected patients
4. Anti-inflammatory treatment: Statins?
What to do ?
Statins to decrease immune activation?
JID 2011
Statins to decrease systemic inflammation
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
Chronic immune activation and inflammation
HIV Infection
and replication
Immune activation: Acquired and Innate Immunity
Chronic inflammation
Immune depletion and immune senescence
Lipodystrophy
Treatment
Age
Personal factors
Non-AIDS defining morbidity and mortality
D’après V Appay J Pathol 2008
Prelamin A : a senescence protein
Involved in progeria
11-year children
Other syndromes of premature aging linked to defects in the
enzyme that maturates prelamin A to lamin A
Accumulation of farnesylated prelamin A
results in accelerated aging
From Liu, Nature Medicine 2005
Prelamin A a biomarker of vascular aging in
human subjects
Aged vascular smooth muscle cells accumulate prelamin A and exhibit
nuclear morphology defects and senescence markers
CD Ragnauth Circulation 2010
Some PIs induce prelamin A accumulation and cellular
senescence in endothelial cells
IL-6 secretion
C Lefèvre ATVB, 2010
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
controls
HIV-infected patients
1
2
3
4
5
6 kDa
prelamin A
lamin A
lamin C
74
72
61
prelamin A
74
(sc-6214)
p53
53
p21WAF-1
21
ß-actin
42
PI
statin
nits)
2.0
1.6
-
-
+
+
HIV+ patients under
NRTI without PI
prelamin A 1.0
0.8
+
-
+
-
+
+
+
+
HIV+ patients
under PI/r
p53
p21WAF-1
The process of prelamin A maturation into lamin A: effect
of statins and farnesyl-transferase inhibitors (FTI)
statin
FTI
C Navarro Hum Mol Gen 2006
Decreased expression of senescence markers in PBMC
from HIV-infected patients under PI/r and a statin
controls
HIV-infected patients
1
2
3
4
6 kDa
5
prelamin A
lamin A
lamin C
74
72
61
prelamin A
74
(sc-6214)
p53
53
p21WAF-1
21
ß-actin
42
PI
statin
protein/ß-actin (arbitrary units)
2.0
-
-
prelamin A
+
0.8
1.2
0.6
0.8
0.4
0.4
0.2
ls
tro
n
o
c
- - + +
+ + - -
+ +
+ +
HIV patients
+
-
1.0
1.6
0
PI statin -
+
0
ls
tro
con
+
-
+
+
p21WAF-1
p53
-
- + +
+ +
- -
HIV patients
+
+
+ +
+ +
ls
tro
con
-
- + +
+ +
- -
HIV patients
+ +
+ +
Hypothetical mechanisms of RTV-boosted PI toxicity
in endothelial cells
Drugs
Inhibition of ZMP-STE24
Accumulation of farnesylated prelamin A
Increased ROS
Cellular senescence
Activation of NFkB
Increased IL6, IL8, MCP-1
Systemic low grade inflammation
Hypothetical mechanisms of RTV-boosted PI toxicity
in endothelial cells: beneficial effect of statins
Drugs
Inhibition of ZMP-STE24
Statins
Accumulation of farnesylated prelamin A
Increased ROS
Cellular senescence
Activation of NFkB
Increased IL6, IL8, MCP-1
Systemic low grade inflammation
Accelerated aging model in HIV infection
role of immune activation/senescence
S Desai and A Landay Curr HIV/AIDS Res 2010
Neurodegenerative diseases , immune activation and
inflammation
S Amor Immunology 2010
Inflammation and activation of stress signals
induces insulin resistance
NFkB
G Hotamisligil Cell 2010
Inflammation and aging
Chronic low-grade inflammation, « inflammaging »
Acute inflammation
Redness
Swelling
Heat
Pain
Local
Resolutive
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
High-fat food, antibiotics, dietary fibers (prebiotics) and bacterial
additives (probiotics) can change the intestinal microflora ecology,
leading to an unbalanced Firmicutes –Bacteroidetes ratio.
M Serino Diabetes Metab 2009
Diabetes, Obesity
J Lyons CROI 2011 # 405