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Regulace znetu: inflammasom a TH17 cytokiny

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Title: Regulace znetu: inflammasom a TH17 cytokiny

1
Regulace zánetu inflammasom a TH17 cytokiny

Pokroky v imunologii
Listopad 2006
Karel Drbal

2
Inflammation

local accumulation of fluid, plasma proteins, and
white blood cells that is initiated by physical
injury, infection, or a local immune response.
Acute inflammation is the term used to describe
early and often transient episodes, whereas
chronic inflammation occurs when the infection
persists or during autoimmune diseases. Many
different forms of inflammation are seen in
different diseases. The cells that invade tissues
undergoing inflammatory responses are often
called inflammatory cells or an inflammatory
infiltrate.

3
Zánet

Souhrn fyziologických reakcí na poruení
integrity organismu, které vedou k ochrane proti
infikování pokozeného místa, k lokalizaci
pokození a zhojení.

4
Projevy lokálního zánetu

zcervenání (rubor)
otok (tumor),
bolestivost (dolor)
zvýení místní teploty (calor)
akutní, chronický (patologický)

5
Charakteristiky lokálního zánetu

Signály - degranulované tkánové írné bunky a
fagocyty, látky uvolnené z ruzných pokozených
bunek.
zvýení permeability cév
zvýení adhezivity endotelií, zachycování
fagocytu, lymfocytu, prunik do tkáne
aktivace koagulacního, fibrinolytického a
komplementového systému
ovlivnení nervových zakoncení (bolest)
zmeny regulace teploty (mediátory - pyrogeny)

6
Systémová odpoved na zánet

horecka (stimulací hypotalamového centra
termoregulace prozánetlivými cytokiny TNF,
IL-1, IL-6, IFN-?, IL-18)
septický ok
anafylaktický ok
exprese proteinu tepelného oku,
produkce sérových proteinu akutní fáze (CRP, SAP
C3 a C4 - opsoniny).
vyplavení a novotvorba leukocytu (leukocytóza).

7
Reparace pokozené tkáne

Eliminace pokozených bunek fagocyty (makrofágy)
aktivace fibroplastických mechanismu
aktivace angiogeneze
regenerace a remodelace tkání
patologicky - fibrotizacní pochody

8
Acute vs. chronic inflammation

Role of chemokines influencespositioning and
timing of inflammatory cells migration(myeloid x
lymphoid infiltration, fibroblast switch,
activated T cells, gdTC)

Buckley Trends Immunol 22199
9
CAVEATS REGARDING INFLAMMATION

Inflammation has multiple humoral, cellular
components, and undergoes amplification.
Defining clinical outcomes from inflammation is
difficult.
Hemostatic activation/thrombin generation is an
inflammatory response, and tissue injury is key.

10
Treatment of Inflammation

Drugs
Aspirin
Nonsteriodal anti-inflammatory drugs
Glucocorticoids
Other therapies
Application of hot/cold
Elevation of inflamed limb

11
IL-1-targeted therapeutics

IL-1 receptor antagonist (IL-1Ra)
treatment of rheumatoid arthritis,
seems to be also extremely effective in patients
with cryopyrin-associated periodic syndromes
(CAPS)

12
Link to wound healing

Blood clot forms and seals area
Inflammation develops
3-4 days foreign material, debris removed
Granulation tissue closes gap
Highly vascularized, fragile
Epithelial cells undergo mitosis
Grows from outside ? in
Macrophages stimulate fibroblasts to enter
Produce collagen and scar
Caps decrease scar red ? white
Scar tissue contains no special structures

13
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14
Triggers

Danger signals
Endogenous usually intracellular - ATP, crystals
of monosodium urate (MSU) and calcium
pyrophosphate dihydrate (CPPD) the causative
agents of gout
Bacterial products equal to TLR ligands,
contradictory experimental results
All triggers are relevant to cellular distress
main source is infection

15
Pathways involved in inflammation induction

Caspases (inflammasome)
NFkB (TLR)

16
Proinflammatory cytokines involved (effector
phase)

IL1-b, IL-18, IL-33
IL1-b processing of pro-IL-1b (stored in
secretory lysozomes) is mediated predominantly by
the IL-1b converting enzyme caspase-1.
rapid activation of caspase-1 and subsequent
processing and release of bioactive IL-1b is
triggered by ATP, which activates the ion-gated
channel P2X7 followed by K efflux.

17
NALP3-inflammasome pathway

more than 700 kDa protein complex that stimulates
caspase-1 and -5 activation to promote the
processing and secretion of proinflammatory
cytokines (IL-1ß, IL-18, and IL-33)
can be activated by endogenous danger signals
as well as compounds associated with pathogens
gain-of-function mutations in the NALP3 gene
cause three autoinflammatory diseases
Muckle-Wells syndrome,
familial cold autoinflammatory syndrome,
neonatal-onset multisystem inflammatory disease.
Collectively, these diseases are called
cryopyrin-associated periodic syndromes (CAPS)
CAPS and RA have been effectively treated by the
administration of an IL-1 receptor antagonist

18
NALP3 (cryopyrin or CIAS1)

member of the CATERPILLER/NOD-LRR/NLR family of
genes

19
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20
Inflammasome pathways

Similar to the activation of caspase-8 or -9 by
the Apaf-1-apoptosome or Fas/CD95-DISC,
respectively, it has been speculated that
caspase-1 may be activated by a molecular
platform termed an inflammasome

Ogura Cell 126659
21
Structure of the inflammasomes
22
Mechanism of action of NALP3
23
Other TLR ligands involved

lipid-A, lipoteichoic acid, lipoprotein, CpG
oligodeoxyribonucleotides, and imidazoquinoline
compounds also prime the cells to activate
caspase-1 in response to ATP
TLR stimulation leads to the induction of genes,
such as NALP3 and caspase-11, that are required
for caspase-1 activation, and that K efflux is
an upstream trigger of NALP3 activation
NALP3-inflammasome seems to be activated by
serial stimulation by TLR ligands followed by K
efflux
IL-1ß secretion induced by ATP is mediated by K
efflux, release of intracellular Ca2 stores, and
the activities of protein tyrosine kinases and
calcium-independent phospholipase A2.

24
Cellular arm of inflammation TH-17 a giant step
from TH1 and TH2

T cells producing interleukin-17 constitute a
previously unknown lineage of CD4 T cells
IL-17-stimulated embryonic fibroblasts
upregulated over 60 unique genes, including many
encoding chemokines
Pathogenic nature of TH-17 cells in patients with
autoimmune and inflammatory diseases
Induced by IL-23

25
Development of TH17 2 models
26
IL-23