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
(No Transcript)
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
(No Transcript)
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

• The IL-6, IL-12, IL-23 and IL-27 family
• Basically all are proinflammatory
• Unique function for IL-23 in T-cell responses
• IL-27 pro- and anti-inflammatory effects

27
IL-17

• The interleukin-17 family of cytokines

28
IL-23/IL-17 axistherapeutic targets for
autoimmuneinflammation
29
Prednáka a clánky dostupné na

• http//www.img.cas.cz/mi/prednasky/