Table 1
Summary of Toll-like receptors and ligands
Receptor Ligands
TLR1-2
Triacyl lipopeptides
TLR2
Lipoteichoic acid, peptidoglycan, porins
Phospholipomannan, B-glucans
Viral hemagglutinin
HMGB1 (high mobility group box)
Viral double-stranded RNA
TLR3
TLR4
Lipopolysaccharide, Manans (fungi),
phospholipids (parasites), viral coat
proteins, heat shock proteins, fibrinogen,
HMGB1, hyaluronic acid, heparan sulfate
Bacterial flagellin
TLR5
Bacterial diacylated lipidopeptides,
TLR2–6
lipoteichoic acid
TLR7
Viral single-stranded RNA
TLR8
Viral single-stranded RNA
Unmethylated CpG (deoxy-cystidylate-
TLR9
phosphate-deoxy-guanylate)
Oligodeoxynucleotide DNA
TLR10
Triacylated lipopeptides
TLR11 Profilin
Ligand origin
Bacteria
Bacteria (Gram-positive)
Fungi
Virus
Host cells
Virus
Bacteria (Gram-
negative)
Fungi
Parasites
Host cells
Bactera (Gram-positive
and Gram-negative)
Mycoplasma
RNA viruses
RNA viruses
Bacteria
DNA viruses
Host cells
Parasites
Toxoplasma gondii
TLR: Toll-like receptor
of specific (mostly pro-inflammatory) genes (Table
2). These intracellular signalling cascades induce
a series of antimicrobial mechanisms. 1,8
Tumour necrosis factor-alpha (TNFα) is one of
the first cytokines released into the bloodstream
after activation. In animal models, it produces
symptoms very similar to septic shock and
administration of anti-TNFα antibodies protects
against death from sepsis. 9 TNFα binds through
the receptors TNFR1 and 2 that are found in most
cells. Binding induces the microbicidal activity of
monocytes; increases production and migration
of PMN; activates coagulation and complement;
alters vascular tone and increased permeability;
and increases protein catabolism and
gluconeogenesis 10 among others, which give rise
the typical symptoms seen in sepsis such as fever,
diarrhoea, metabolic acidosis, neurotoxicity,
cachexia and CID. 11 Interleukin-1 (IL-1a and IL-1b)
act synergistically with TNF. IL-17 has also been
implicated in the pathophysiology of sepsis.
Antibody neutralisation of IL-17 in mouse models
results in decreased organ damage and improved
survival. 12 Micro-RNA also plays an important role
in the inhibition of TLR/MyD88 feedback of
signalling. 13
Phospholipase A2 activation in response to
various inflammatory stimuli, including C5a,
TNF-a, IL-1 or IL-6, generates arachidonic acid (AA)
from membrane phospholipids. AA is metabolised
via two pathways: the cycloxygenase (COX)
pathway, which stimulates the synthesis of
prostaglandins and thromboxanes; and the
lipoxygenase (LO) pathway, responsible for the
production of leukotrienes. COX and nitric oxide
synthase are two of the main enzymes that
mediate cardiovascular dysfunction and
contribute, together with LO, to the progression
to multiorgan failure in the septic patient. 14–16
NF-κB increases the expression of plasminogen
activator inhibitor type 1 (PAI-1) and inhibits
fibrinolysis, in addition to releasing cytokines
that inhibit the expression of thrombomodulin,
an important factor for the activation of protein C
(inactivates pro-coagulant factors) and the
decrease of the pro-coagulant activity of
thrombin. 17,18
Iron metabolism is affected in sepsis both at
the systemic and at the cellular level. Its ability
to change oxidation states makes it an important
cofactor in the transfer of electrons and oxidation
reduction reactions in metabolic and signalling
pathways. It is known that iron overload is
associated with greater susceptibility to bacterial
infections and high levels of ferritin have been
linked to poor prognosis. 19,20
Altered cellular function of neutrophils,
macrophages and monocytes are also associated
with poor prognosis in patients with sepsis. Late
neutrophil apoptosis and prolonged response of
neutrophils are associated with increased organ
damage, including acute respiratory distress
syndrome, and reduced survival. 21 Both
programmed cell death receptor 1 (PD-1) and
adenosine receptors seem to play an important
role. 22,23 Reactive oxygen species released by
neutrophils are part of the positive feedback
of the inflammatory response and cause both
endothelial and mitochondrial dysfunction that
contributes to the multi-organ failure. The
decrease in the expression of the cell surface
receptor HLA-DR in monocytes has been shown to
be a predictor of nosocomial infection in patients
with sepsis. 24 TH17 cells activate neutrophil
responses and are increased in patients who
survive sepsis. 25 Natural killer T cells are potent
producers of IFNg and other pro-inflammatory
cytokines and have cytotoxic effector functions.
They promote the sepsis inflammatory response
and are associated with increased mortality in
elderly septic patients. 25 Mucosal-associated
invariant T cells secrete IL-17 and IFNg after an
infection. A decrease in the number of these cells
correlates with the development of nosocomial
infections. 26
Alteration of adaptive immunity in sepsis
The adaptive immune system is characterised by
its specificity and by having a memory
Table 2
Genes transcribed after activation of NF-κB
Types
Genes transcribed
Cytokines
G-CSF, GM-CSF, TNFa, TNFb, IL-1a, IL-1b, IL-2, IL-3
IL-5 , IL-6, IL-12, IL-18
Chemokines
MIP-1, MIP-2, GROa, GROb, GROg, RANTES
TF, PAI-1
Coagulation factors
Adhesion molecules
E-selectin, P-selectin, VCAM-1, ICAM-1, ELAM,
MadCam1
Immunoreceptors
IL-2RA, MCH
Acute phase proteins
C reactive protein, LBP
Enzymes
iNOS, COX2, PLA2, LOX5, c3, MMP
Costimulatory molecules B7.1 (CD80), B7.2 (CD86)
G-CSF: granulocyte colony stimulating factor; GM-CSF: stimulating factor of granulocyte and monocyte-type
colonies; TNF: tumour necrosis factor; IL: interleukin; MIP: macrophage inhibitor protein; GRO: growth-related
oncogene; RANTES: normal T cell expressed and secreted; TF: tissue factor; PAI: plasminogen activator
inhibitor; ELAM: endothelial cell leukocyte adhesion molecule-1; IL-2RA: receptor A of IL-2; MCH: major
histocompatibility complex; LPB: LPS binding protein; iNOS: nitric oxide synthase; COX: cyclooxygenase; PLA:
phospholipase A; LOX: lipoxygenase; C3: coagulation factor 3: MMP: matrix metalloproteinases.
12
HHE 2018 | hospitalhealthcare.com