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THE INFLAMM-AGING THEORY
An Evolutionary Perspective onImmunosenescence and Aging
Dr. J. Alijotas-Reig*¶ ♦, R. Kandhaya-Pillai¶.
*Systemic Autoimmune Diseases Unit. Service of Internal Medicine-I. Vall d’ Hebron University Hospital. UAB (Prof. M. Vilardell-Tarrés)
¶ Aging Basic Research Unit. Molecular Biology and Biochemistry Research Center for Nanomedicine. CIBBIM-Nanomedicine. Vall d'Hebron University Hospital. Research Institut (VHIR)
♦ Department of Medicine. Faculty of Medicine. Universitat Autònoma de Barcelona. Spain
2012-UPDATED
Maybe, in that moment, he loved the life more than ever…… What he desired were the same answers we all look for.
• Where do I come from?
• Where do I go?
• How long am I going to stay?
Blade Runner. Ridley Scott, 1982
For human being, aging have more questions than answers.
TEORIAS MOLECULARES Y GENÉTICASMutaciones somáticas y alteraciones en la reparación del ADNErrores catastróficos de transcripción o de translocaciónAlteraciones o diversidad de gerontogenes (LAG-1)Telómeros / Longuitud telomerasasPresencia de apoE4Mutación del precursor de la beta amiloide
TEORÍAS CELULAREST. de HayflickT. de los radicales libres (R.O.S)T. mitocondrialT. de la glicosilación proteicaT. de las membranas
TEORÍAS DE SISTEMAST. inflamatoria, (INFLAMMAGING THEORY)
T. Neuroendocrina
PRINCIPALES TEORIAS SOBRE EL ENVEJECIMIENTO
Could aging be a chronic low-grade inflammatory state?
InflammationSenescence
Cancer
Autoimmunity
INFLAMMAGING THEORYChronic low-grade inflammation
Pro-inflammatory cytokines Frailty
Atherosclerosis
Parkinson disease
Alzheimer disease
Osteoarthritis
Osteoporosis
Insulin resistance/type 2 diabetes mellitus
Sarcopenia
Predisposed genetic background Predisposed genetic backgroundMacrophage
INFLAMMAGING THEORY
Coined by Claudio Franceschi * in 2000
Ageing is accompained by a low-grade, systemic up-regulation of the inflammatoryresponse.
Chronic low-grade inflammatory status
Senescence age-associated diseases
Franceschi et al, Ann NY Acad Sci, 2000
OsteoporosisOsteoarthritisSarcopeniaAlzheimerDiabetes MellitusArtheriosclerosisParkinson disease
INFLAMMAGING THEORY
This inflammatory state is characterised by:
1. Low grade
2. Controlled
3. Asymptomatic
4. Chronic
5. systemic
INFLAMMAGING THEORY
Internal and environmental inflammatory stimuli
individual background
Pro-inflammatory cytokines
cytokine polymorphisms
Reactive Oxigen Species (ROS) oxidative damage
Autoantibodies
pro-inflammatory cytokines
INFLAMMAGING, CYTOKINES AND AGING
The most important age-associated diseases share a common inflammatory background:
TNF-α, TNF-β, IL-1β, IL-6, IL-10 are the most proinflammatory involved cytokines
Certain cytokine polymorphisms have been related to aging:IL-10 (1082 G/A)TNF-αIL-6 (174 G/C)
Aging: gender differences
Role of Toll-like receptor 4 (TLR4) and Heat shock proteins (HSPs)
INFLAMMAGING, CYTOKINES AND AGING
• Inflammation, metabolism and aging:
muscle mass
adipose tissue
mitochondrial function
TNF-αLeptinaIL-1IL-6IFN-γIL-8FibrinogenAngiotensinogenCRPPAI-IMetallothioneinComplement factor 3Monocyte chemotactic protein-IMacrophage inflammatory protein-ISAA protein
B.M.I
Cell energy R.O.S productionCell apoptosis
DNA maintenance DNA damage
IL-6 / TNF-α / IL-1
AGEING
SISTEMA INMUNE Y ENVEJECIMIENTO
Alteraciones en la producción de citocinas:
predominio de Th1 sobre Th2
IL-2 ? / IL-2R IL-3?
IL-6 IL-4
α-TNF IL-5
IL-10
APCs IL-1
nTreg ? pTreg?
Immunological polymorphismsprofiles and ageing
• ↑ IL-2• ↑ IL-7 +Zn• ↑ IL-4• ↑ IL-10• ↓ TNFα• ↑ CD45RA+ y ↓ CD45RO+• ↓ IL-6• ↓ IFN-gamma• ↑nTreg (CD4+CD25-Foxp3+)
↓ Th1 / ↑ Th2 / ↑ nTreg
Down-regulation
IMMUNOSENESCENCE
Thymosuppressive Thymostimulatorycytokines cytokines
steroids LIF IL-7IL-6 KGF
Oncostatin MTSLP
hGHLeptinIL-10
ThymusRobustThymusAtrophied
thymus
IL-1, IL-3, TGF-β
DNA-anti-apoptotic Bcl-2
AGEING: IS IT AN AUTO-[INNATE]-IMMUNITY SUBCLINICAL SYNDROME?
Classical inflammatory signs
Redness (rubor)
Swelling (tumor)
Pain (dolor)
Warm (calor)
Loss of function (functio lesa)
Inflammaging cardinal signs
Low-grade
Controlled
Asymptomatic
Chronic
Systemic
Giunta S. Immunity&Ageing, 2007
May be inflammaging a new chapter of autoimmunity?
INFLAMMAGEING THEORY
Clasical autoimmune diseases adaptive immunity
New “innate” autoimmune syndrome innate immunity
“Inflammaging may constitute the subclinical paradigm of new type of autoimmunity, namely that arising from an auto-immune inflammatory response of the innateimmune-syndrome an old actor of immunity and yet a new actor of autoimmunity”*
*Giunta S. Immunity&Ageing 2006
CELLULAR SENESCENCE CAN BE INDUCED BY
SENESCENCE CELLS
MORPHOLOGICAL CHANGESCells become largerCells display increasedgranularityCells flatten outCell borders tend to vanish
SENESCENCE CELLS
BIOCHEMICAL CHANGES(beta)galactosidase activity +
Questions to be answered:
In an in-vitro cellular model, may low-level proinflammatory cytokines provoke premature cell senescence?
Which are the intracellular pathways used, through which proinflammatory cytokines provoke their undesirable cell actions regarding cellular senescence?
Which is/are the gene/s that regulate/s the final expression of these proinflammatorybackground or what gene/s may act as a protective against the former proinflammatory status? (robust or frail gene ?)
Molecular Regulation of Inflammatory Pathways in Human Endothelial Cells Senescence
To establish a cellular model of senescence by inflammatory signals
To study the gene expressional changes and signaling pathwaysregulated during senescence.
Dissect the molecular role of inflammatory pathways during senescence
To determine the miRNA architecture in senescence
Molecular Regulation of Inflammatory Pathways in Human Endothelial Cell Senescence
Resultados
Tto crónico con TNFα induce senescencia prematura en células HUVEC
↑ROS en HUVEC en respuesta a estimulo crónico con TNFα
Diferencias en la expresión de micromatrices de RNA
Diferencias en la expresión de miRNA durante la senescencia inducida por TNFα
β-GalP53, p21BrdU /IPH2AX
H2AX
Sobre expresión de 341 genesExpresión suprimida de 40 genes(transcritos en 5 clústeres)
Importante: circuito TNFα IL-6 STAT1/STAT3 (via p38/MAPK)
Molecular Regulation of Inflammatory Pathways in HumanEndothelial Cell Senescence
Diferencias en la expresión de miRNA durante la senescencia inducida por TNFα
HUVEC “jovenes”/HUVEC senescentes (rep)
↑ miR 217↑ miR 145
↓ miR18a↓ miR21
HUVEC-TNFα/HUVEC sen replicativa
↑ miR 146a↑ miR 21↑ miR 195
↓ miR 7c
Dianas potenciales: KIF2C, SPC25, CDC25BNCAPG, RAD51AP1,HMGA2, KIF2C, CEP55/G0S2
Resultados:
Molecular Regulation of Inflammatory Pathways in HumanEndothelial Cell Senescence
La estimulación crónica con TNFα se relaciona con la senescencia prematura.
La activación STAT1/3-IL6 promueve un asa amplificadora autoregulada que perpetua la vía inflamatoria.
Además de STAT1/3, la via JAK2 también juega un rol importante (doble via JAk2/STAT1/3).
La senescencia inducida por TNF-α se acompaña de modificaciones en la expresión de diversos genes responsables del control del ciclo celular.
Determinadas alteraciones a nivel del miRNA sugiere su posible papel en la regulación de la senescencia.
CONCLUSIONES:
Inflammation, autoimmunity and ageingAPOPTOSIS, mediated by two major pathways:
Extrinsic Intrinsic
death receptor-mediated (TNFRs) mitchondria mediated
(CD95)
trimerization of DD poor studied in elderly
pro-caspases
caspases
Inflammation, autoimmunity and ageing
APOPTOSIS IN AGINGIncreased apoptosis in T cells, CD4+ and CD8+
↑ sensitivity CD95-CD95L ↑ activation caspase-8 /3
↑ FADD
↑sensitivity to TNF-œ -induced apoptosis
(to analize the proposed mechanisms, see figure 3)
Inflammation, autoimmunity and ageingRole of apoptotic cells in the regulation of inflammation and
changes in aging (I)
Apoptotic cell death and clearance of dead cells is essential to homeostasis
Clearance of apoptotic cells have an anti-inflammatory effects
Ie: co-cocultures between apoptotic cells and APCs
Apoptosis regulates the cytokine profile
Slow apoptotic cell clearence undergo secondary necrosis
Dendritic cells (APCs) are basic in large scale phagocytosis apoptotic cells
Inflammation, autoimmunity and ageingRole of apoptotic cells in the regulation of inflammation and
changes in aging (II)
Apoptotic cell death and clearance of dead cells is decresed in elderly
Phagocytosis of apoptotic T-cells by dendritic cells is decreased
TNF and IL-6 of apoptotic cells is increased (old/young)
Co-cultures failed to inhibid the production of pro-inflammatory cytokines
Accumulation of apoptotic cells, inducing secondary necrosis and inflammation
DCs may uptake self-Ag derived of apoptotic cells or 2 necrosis to induce
autoimmunity.
Failure in apoptotic regulation: INFLAMMATION AND
MECHANISMS OF IMMUNOSENESCENCE
Three major models of human accelerate immune aging
• Latent CMV infection• HIV infection under highly active antiretroviral therapy (HAART)• Chronic autoimmune disease
Chronic or latent viral infections CMV / HIV
Lymphocyte exhaustionAccelerate immune aging
MECHANISMS OF IMMUNOSENESCENCEThymic involution accelerates immune aging