Inflammation
Characteristics of PMN & monocytes/macrophages
Diapedesis, chemotaxis, & phagocytosis
Mononuclear phagocyte system
Inflammatory response to injury/infection
Signaling: PAMPs & DAMPs, PRR (TLR4), & NFκB
Vasodilation & increased capillary permeability (role of mast cells)
Endothelial cell & PMN activation: role of macrophages
PMN-endothelial cell adhesive interactions
Resolution of the inflammatory response
PMN apoptosis
Role of macrophages
Guyton: chapter 33, pp. 455 - 462
Injury/infection → acute inflammation
dynamic protective response of vascularised tissue
Infection or
Injury?
& IL-8
Phagocytic leukocytes and their role in inflammation
Leukocytes*: granulocytes & agranulocytes
Polymorphonuclear neutrophils (PMN)
Monocytes/macrophages
Phagocytes
μl
* leukocytes: no hemoglobin – white blood cells (WBC)
Life span of neutrophils (PMN)
Myelopoiesis in bone marrow
Mature
5 – 7 days
7 – 9 days
4- 8 hrs 4- 5 days
Storage pool in bone marrow > circulating pool
How do PMN enter injured/infected tissue?
Neutrophil diapedesis & chemotaxis
Diapedesis: PMN migrate between
endothelial cells
along a
chemotactic gradient established by
chemicals generated at the site of
injury/infection
Examples:
Chemokines (IL-8)
Bacterial products (f-MLP)
Leukotrienes (LTB₄)
Life span of PMN
Bone marrow
Mature
5 – 7 days
Deterioration
due to age
*
Clearance from blood:
Senescence, apoptosis
mononuclear phagocyte system
liver, spleen, bone marrow
7 – 9 days
4- 8 hrs 4- 5 days
Clearance from tissue:
apoptosis → efferocytosis
mononuclear phagocyte system
Life span of monocytes/macrophages
Immature
phagocytes
↓
8 hrs
↓
Monocyte
10 – 20 hrs
months
Mature
Phagocytes
(↑ size)
Sentinel cells
More efficient phagocytes than PMN: more material and larger material
Mononuclear phagocyte (reticuloendothelial) system: sentinel cells
Recognition and removal
of pathogens & debri
histiocytes
Removal of
senescent WBCs
Recognition and removal
of pathogens & debri in lymph
Phagocytosis: digestion
Cell debri
Macrophages can phagocytose more material than PMN
PMN undergo apoptosis soon after multiple bouts of phagocytosis
Macrophages can survive for a longer period of time
Phagocytosis: killing
Phagocytic NADPH oxidase
Enzymes & proteins
Enzymes:
Elastase
ECM degradation
Lysozyme
GAG degradation (bacterial wall)
Other lysosomal hydrolases
Anti-microbial proteins:
Lactoferrin
binds iron
Defensins
antibiotic
Injury/infection → acute inflammation
dynamic protective response of vascularised tissue
Bacteria
Cell debri
& IL-8
Phagocytic leukocytes and their role in inflammation
Chemical signals
Infection: bacterial components
Bacteria
Cell debri
pathogen-associated molecular patterns
PAMPs
recognition of “non-self”
Sterile injury: danger signals - “alarmins”
material released from dead/damaged cells
damage-associated molecular patterns
DAMPs
recognition of “damaged self”
Chemical signals
Infection: bacterial components
pathogen-associated molecular patterns (PAMPs)
Bacteria
Cell debri
Sterile injury: material released from dead/injured cells
damage-associated molecular patterns (DAMPs)
PAMP
PRR
Receptors on sentinel cells:
Pattern recognition receptors (PRRs)
DAMP
Sentinel cells:
Macrophages
Mast cells
Major receptor for PAMPs & DAMPs
Toll-like receptors (e.g., TLR4)
Chemical signals: infection
Infection: bacterial components
pathogen-associated molecular patterns (PAMPs)
prototype PAMP: lipopolysaccharide (LPS)
PAMP
PRR
1) Rapid response
vasoactive mediators
PAF, PGI2
2) Delayed response
IL-1, TNF-α
pro-inflammatory chemokines
IL-8
Mast cells:
Histamine
Chemical signals: sterile injury
Sterile injury: material released from dead/injured cells
damage-associated molecular patterns (DAMPs)
Prototype DAMP:
high mobility group box -1
(HMGB1)
– nuclear protein
Cell signaling
Infection: bacterial products
pathogen-associated molecular patterns (PAMPs)
Sterile injury: material released from dead/injured cells
danger-associated molecular patterns (DAMPs)
Receptors on sentinel cells:
PAMP
PRR
Pattern recognition receptors (PRRs)
Major receptor for PAMPs & DAMPs
Toll-like receptors (TLR4)
DAMP
Sentinel cells:
Macrophages
Mast cells
Convergence of DAMPs and PAMPs
on
“common final pathway”
Receptors on sentinel cells:
Pattern recognition receptors (PRRs)
Major receptor for PAMPs & DAMPs: Toll-like receptors (TLR4)
PAMPs
TLR4
DAMPs
TLR4
Macrophage & mast cells
Cytokines: TNF-α, IL-1
Chemokines: IL-8
1)
2)
3)
4)
5)
6)
NLS
pro-inflammatory
NFκB bound to IκB
genes
TLR4 activates IкB kinase
IкB kinase phosphorylates IкB
Phosphorylated IкB disassociates from NFкB & is degraded (proteasome)
NFкB translocates to nucleus
NFкB initiates transcription of cytokines & chemokines