Resolution of Inflammation Flashcards
What is homeostasis in terms of inflammation?
Balance between
-Damage, inflammation, immunity
with
-Resolution & wound healing
What are the 3 basic steps to reinstate homeostasis after injury/infection?
1
2 = switch off all inflammatory activation signals - always needed as inflammation = 1st thing happens in body when is damage/danger
3 = not always needed - as is not always a wound - can have inflammation without wound!
NOT NECESSARILY CHRONOLOGICAL!
Why for an anterior cruciate ligament injury would there be no adaptive immune response even when there is inflammation?
Epithelial barriers not breached - no pathogen/PAMPs enter - so inflammation is only triggered by DAMPs = sterile inflammation/damage
What 3 things are involved in ‘1. terminating adaptive immune responses’?
What 3 things are involved in ‘2. inflammation resolution’?
Removal of pro-inflammatory factors
–> these factors must be short-lived so don’t constantly activate inflammation
(–> in pro-inf diseases - use antibodies to ‘mop up’ pro-inflammatory cytokines (TNFa, IL-6, IL-1B))
What is a disadvantage of prolonged inflammation?
Decreases life chances in future - i.e., acts as a survival method for the now & suffer for it in future = long term consequences
–> inflammation becomes a disease in its own sense
What are the 3 things involved in ‘3. wound healing & repair’?
Replace tissue matrix
–> replace w/ something that has high tensile strength/elasticity or whatever is needed in tissue
Why is Th response turned off?
Th = central administrators of whole imm resp - so if turn off these = turn off cytotoxic responses, macrophage responses
Which types of helper T cells are pro-inflammatory & which are anti-inflammatory?
Th1 = pro-inflammatory
Th2 = anti-inflammatory (also role in clearing parasites)
Describe how T cells are activated & ultimately removed (as effector cells) - as part of ‘1. terminating adaptive immune responses’?
-PAMPs/DAMPs activate DCs
-DC activates naïve T cells (CD4 or CD8) = 3 signals: antigen, co-stimulation, cytokine
-IL-12 cytokine signal from DC to CD4 T cell = forms Th1
-Th1 produces IFNy
-IFNy from Th1 = activates macrophages (to undertake phagocytosis - if necessary for infection)
-But if any of these 3 signals is no longer present (antigen, costimulation, cytokine) = T cell phenotype changes OR T cell dies (maybe as all bacteria = killed - no antigen - signal 1 is gone, & when remove PAMPS = reduces co-stim, & when DC is not recieving PAMPS - cytokine signal 3 is IL-10 not IL-12!)
What are the 4 possible outcomes to T cells after responding to an antigen - all in order to remove the T cell?
*Th1 can change to Th2 (as this = anti-inflammatory phenotype)
*Anergy = irreversible state where T cell can’t be activated - even @ optimal conditions = occurs if is no co-stim - seeing antigen but no co-stim (risk of autoimmunity)
*Exhaustion = temporary inactive state of T cell
*Activation-induced cell death = excited cells (@ start of imm resp) die (as are metabolically spent up) - leads to transient lymphopenia
What is involved in the changing of T cell phenotype from Th1 -> Th2?
-DC produced IL-4 (as the polarising cytokine to the T cell)
-CD4 T cell is caused to differentiate to Th2
-Th2 expresses the GATA3 TF - so produces:
IL-4
IL-5
IL-13
–> which activate eosinophils, macrophages, mast cells
-IL-13 = leads to production of TGFB - as IL-13 makes tissue cells (macrophages) which produce TGFB = anti-inflammatory cytokines (leads to Treg production - is polarising cytokine - so when is environment w/ lots of TGFB - &/or IL-10 = iTreg form from naïve T cells)
What are the 2 types of regulatory T cells (Treg)?
-Natural/thymically derived Treg (nTreg) - maintain tolerance at all times
-Inducible Treg (iTreg) - generated from naïve cells in tissues & reduce function of DCs & other imm cells (ONE SHOWN ON CYTOKINE TABLE!)
–iTreg made in LN & enter tissues later into response when is more TGFB from Th2 or more IL-10 (don’t become Th1 or Th2) - these iTreg help drive resolution
–> BOTH express CD4, CD25, CTLA4
-Only nTreg expresses CD62L
-ALL express TF - FOXP3
Importance of iTreg?
Need to be able to make extra Tregs under certain circumstances - i.e., to drive inflammation resolution when is high TGFB or IL-10
What types of T cells are made in the thymus?
-Th
-Tc
-nTreg - present in body already as nTreg (unlike iTreg which comes from naive T cells in tissues)
Name the only difference between the ‘molecules’ expresses by the 2 types of Treg?
ONLY nTreg (natural) express CD62L
How are T regulatory cells made - part of ‘1. terminating adaptive immune responses’?
“CD4+ Tconv cells isolated from lymphoid organs and peripheral blood can be induced to express Foxp3 in vitro by T cell activation in the presence of TGF-β1 and IL-2”
-Environment bathed in/high in IL-10 &/or TGFB = naïve T cell is driven to form iTreg
-iTreg sequester (capture/eat) IL-2 from DCs = prevents any T cell proliferation of other cell types & also iTreg pull DC activation molecules into their own immune synapse so other T cells can’t use these (removes co-stim molecules)
-Causes expression of FOXP3 TF = IL-10 & TGFB
–> these are anti-inflammatory cytokines = act as off signals
-So iTreg suppresses other effector T cells
What is the other type of cell that regulates the adaptive immune response - as part of ‘1. terminating adaptive immune responses’?
Regulatory B cells
What is the aim of ‘1. inflammation resolution’?
Remove the 5 signs of inflammation
Name the 3 main mediators of ‘2. inflammation resolution’?
-Alternatively activates M2 macrophages
-Apoptotic neutrophils (as dying neutrophils = strong signal to inflammatory system that have begun to remove ‘problem’ so must start switching off inflamm)
-Cytokines - IL-10 & TGFB
What are some specific pro-resolving chemical mediators to resolve inflammation?
-Lipid mediators (lipoxins, resolvins, protectins & maresins) = diff metabolites of lipid - bind to diff recs - turn off tissue cells & macrophages & neutrophils from producing pro-inf cytokines
-Proteins (annexin A1, galectins) & peptides gaseous mediators including hydrogen sulphide & CO - work same as lipids above
-Purine (adenosine)
-Neuromodulators released under control of vagus nerve - stimulating vagus nerve = turns off inflamm
–> all turn off inflammation
How can apoptotic neutrophils initiate the transition to resolution of inflammation?
-Presence of pathogen (PAMPs) & pro-inf cytokines maintain neutrophil survival (= survival signals) & influx into tissue
-Infection = cleared - stimulus producing pro-inf cytokines = lost - neutrophils undergo apoptosis
-Apoptotic neutrophils secrete signals - attract macrophages & inhibit neutrophil recruitment
-Macrophages attracted to & recognise phosphatidylserine on outer memb (is flipped from inner to outer memb) of apoptotic neutrophil = ‘flags’ to macrophages that neutrophil is dying
-Get efferocytosis = phagocytosis of neutrophil by macrophages
–> this changes macrophage phenotype (due to phosphatidylserine) - macrophage produces factors linked to inflamm resolution - M1 to M2 macrophage (M2 = anti-inflammatory phenotype)
-High levels of TGFB from macrophages = induces recruited T cells = iTreg (cycle…)
What is the role of phosphatidylserine?
Opsonising signal - to induce efferocytosis (phagocytosis of neutrophils) by macrophages
–> & removes pro-inf signals - by changing phenotype of macrophage from M1 -> M2
What are the 3 types of macrophages?
-M1 macrophage - pro-inflammatory
-M2 macrophage - anti-inflammatory
-Efferocytosing pro-resolving macrophage
Are there actually set types of macrophage?
No - is a spectrum of macrophage function = based on what can study in lab
-When macrophages in inflamm situation = act as M1s
-Depending what happening in tissues = become more specific efferocytotic macrophage function
-Overlap between - M2 & efferocytosing - but slight differences
Which types of macrophages are for inflammation resolution & wound healing?
M2 & efferocytosing pro-resolving macrophages
What are M1 macrophages?
-Pro-inflammatory
-Involved in host defences - these are ones previously learnt about - when is active need for inflammation &/or resolve infection
-Produce NO
ACTIVATION:
-PAMPs bind DC
-DC activates T cell = Th1 (3 signals - polarising cytokine = IL-12)
-Th1 produces IFNy
How are M1 macrophages activated & what do they do?
-Activated by DAMP, PAMP (LPS - bact cell wall component) OR pro-inf cytokines (from Th1)
Activating pro-inf cytokines:
–> TNFa = from Th1
–> IFNy = from Th1
-M1 macrophages produce:
chemokines, IL-6, IL-1B, IL-12 & TNFa = pro-inf cytokines to prolong inflammation as is needed!
*IFNy from Th1 causes M1 production & M1 also produces IL-12 which in turn activates more Th1
-IL-12 activates NK cells & Th1
-NK & Th1 produce IFNy
-NK produces TNFa
-Involved in host defences against infection
-NK derived IFNy activates M1 to produce NO
-Produce nitric oxide - for bacterial killing
What are M2 macrophages?
-Anti-inflammatory
-Wound healing
-Angiogenesis (blood vs formation)
-Reduced MHC II & inhibit T cell responses
How are M2 macrophages activated & what do they do?
ALTERNATIVE MACROPHAGE ACTIVATION!
-Arise after exposure to cytokines from Th2 –> IL-13 & IL-4 (when infection is ‘dying down’)
-Promote angiogenesis (blood vs formation)
-DO NOT produce nitric oxide for bacterial killing
-Express reduced MHC II & inhibit T cell responses
-Produce growth factors - matrix metallo-proteinases & Vascular Endothelial Growth Factor (VEGF), & get IL-10
How are Efferocytosing pro-resolving macrophages activated & what do they do?
-Arise after efferocytosis of apoptotic neutrophils - as these macrophages are the ones that efferocytose apoptotic neutrophils & then undergo a change in phenotype to this type of macrophage
-IL-10 in environment
-These efferocytosing pro-resolving macrophages produce: VEGF, IL-1RA, IL-10, TGFB
-Secrete repair mediators
-Activate fibroblasts & stromal cells to make CT
-Recruit Tregs (due to TGFB production)
-Increase angiogenesis
What types of helper T cells activate what types of macrophage?
Th1 = M1
Th2 = M2 ‘alternative macrophage activation’
Summarise the entire process - not great detail - just stages.
- Injury/infection = PAMPs &/or DAMPs
- Tissue resident cells release pro-inf cytokines & chemokines
- DCs = activated by DAMPs/PAMPs
- Monocytes recruited - form M1 macrophages which produce pro-inf cytokines/chemokines
- Neutrophils recruited by these substances
- Phagocytes - phagocytose pathogen = release more inflammatory signals recruits T cells - by DCs (depends on if inflamm needed to continue or not - if is = Th1, if not = Th2) —> so Th1 has 4 options: switch to Th2, anergy, exhaustion or activation-induced cell death - once Th1 have responded to pathogen if switch to Th2 these then activate M2!!!!!
- Pathogen killed = cells die by neglect or exhaustion (involves T cells)
- Apoptotic neutrophils present phosphatidylserine on memb - attracts/recognised by macrophages
- M2 macrophages & apoptotic neutrophils prevent further neutrophil infiltration
- Macrophages efferocytose apoptotic neutrophil - causes phenotype of macrophage to change = M2 - anti-inflamm type & efferocytosing pro-resolving type too!
—> M2 macrophages (come from Th2 - by switching of Th1 to Th2) produce IL-10 which creates environment for efferocytosing macrophage activation - M2 & efferocytosing pro-resolving macrophages - produce VEGF (& M2 makes matrix metalloproteinases) = promotes tissue/wound repair
- Loss of pro-inf cytokines & by producing TGFB (&/or IL-10) from efferocytosing pro-resolving macrophage = causes naïve T cells to become iTreg
- iTreg = reduce DC & other imm cell function
LOOK AT STEP 8 IN IMAGE!
Fill in.
Summarise TGFB roles?
What are the 3 basic stages to give restoration of tissue architecture & function after injury?
3 OVERLAPPING PROCESSES!!!
2 = as inflammation is starting to end - get more angiogenesis, granulation tissue = tissue get before scar is fully healed, blood vs needed as provide nutrients for CT formation
3 = wound is closed (prevents further infection) - not necessarily correct CT or cells to return to normal so maturation is where replace temporary fix with permanent one
Compare the temporary wound healing of the extracellular matrix fix to the permanent one?
-Temporary = clot - by fibrinogen
-Permanent = mix of structural, adhesion, compressive resilience components - collagen, elastin, integrins, fibronectin, proteoglycan, hyaluronan –> gain during maturation stage
How are the 2 routes of wound healing achieved?
Stimulus = knife, bacteria…
Cells can regrow = i.e., get parenchymal cells growing (functioning cells for that tissue type)
What are the 3 different types of tissue that determine whether parenchymal cells can regrow?
-Continually dividing tissues - will continually regenerate - no need for damage to trigger this
-Quiescent tissues - can regenerate, just not continually - damage must trigger regrowth
-Non-dividing tissues = no regeneration ability in this tissue type
What happens during chronic inflammation?
-Continued release of pro-inf cytokines can = damaging & have systemic effects
-Damaged blood vs produce bradykinins = inc vascular permeability & can stimulate nerves = pain
-Inflammation can become chronic leading to debilitating diseases
What happens if inflammation resolution doesn’t occur correctly?
Summarise the 3 overall stages of resolving inflammation (or just injury, any sort of damage) - say what they are & what occurs in them?
