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Innate ImmunityReview
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TOLL-LIKE RECEPTORS (TLRS)
TLRs were the first PRRs to be identified and remain the best char-
acterized. Signaling by TLRs initiates key inflammatory responses
and also shapes adaptive immunity.
All TLRs (10 in humans and 12 in mice) are type I transmembrane
proteins characterized by an extracellular leucine-rich domain
and a cytoplasmic tail that contains a conserved Toll/IL-1 receptor
(TIR) domain. TLRs recognize various PAMPs, including lipid-based
bacterial cell wall components such as lipopolysaccharide (LPS) and
lipopeptides; microbial protein components such as flagellin; and
viral or microbial nucleic acids such as single-stranded or dou-
ble-stranded RNA, and CpG DNA. TLR ligands also include DAMPs
liberated from damaged or dying host cells, including nucleic acids
and proteins.
TLRs initiate shared and distinct signaling pathways by recruiting
different combinations of four TIR-domain-containing adaptor
molecules: MyD88, TIRAP (Mal), TRIF and/or TRAM. These signal-
ing pathways activate the transcription factors NF-kB and AP-1,
leading to production of inflammatory cytokines and chemokines.
They also activate interferon regulatory factors (IRFs) such as IRF3
and IRF7, which lead to production of type I interferons (IFNs) and
upregulation of interferon-stimulated genes (ISGs).
TLRs can be organized by cellular localization: TLRs 1, 2, 4, 5 and
6 are cell-surface receptors, whereas TLRs 3, 7, 8, 9 and 13 are
endosomal receptors. This localization mirrors the chronology
of PAMP contact with host cells: the surface TLRs detect surface
components from incoming microbes, whereas the endosomal
TLRs detect nucleic acids released by pathogens into the host cell
cytoplasm. Intriguingly, upon activation, TLR2 and TLR4 move from
the surface into endosomes.
An exceptional case among TLRs is TLR10, a surface TLR that pro-
vides anti-inflammatory, rather than pro-inflammatory, responses.
It does this by negatively regulating other TLR pathways.
The innate immune system is an evolutionarily conserved system acting as a first-line of defense against exogenous and endogenous
threats to the host, such as pathogenic infection, tissue damage or cancer. It includes diverse cells such as macrophages, dendritic cells
(DCs), neutrophils, natural killer (NK) cells and innate lymphoid cells (ILCs). The destruction and clearance of invading pathogens, and the
resolution of other threats to the host, requires complex coordination of multiple innate immune pathways.
Importantly, the innate immune system not only precedes the highly specialized adaptive immune system chronologically, but also enables
the long-lasting immunological memory characteristic of adaptive immunity. This is done partly through the work of innate antigen-pre-
senting cells (APCs), which interact with adaptive immune components such as B cells and T cells.
In order to detect and gauge threats, innate immunity employs an arsenal of specialized receptors. Chief among these are the numerous
pattern-recognition receptors (PRRs), which are found at varying levels in immune and non-immune cells alike. The cognate ligands of
PRRs comprise pathogen-associated molecular patterns (PAMPs), which are found exclusively on or in viruses, bacteria, fungi and other
microbes, and danger-associated molecular patterns (DAMPs), which are released by damaged or dying host cells.
The recognition of PAMPs and DAMPs by PRRs generates an acute inflammatory response. This involves secretion of cytokines and
chemokines, production of antimicrobial peptides, triggering of apoptotic or pyroptotic cell death, induction of autophagyand recruitment
of phagocytic cells.
The main PRR families are the Toll-Like receptors (TLRs), the NOD-Like receptors (NLRs), the RIG-I-Like receptors (RLRs), cytosolic DNA
sensors (CDSs), the C-type lectin receptors (CLRs) and inflammasomes. Many of these processes induce, or are regulated by, autophagy.
2017
TLR PRINCIPAL LOCALIZATION
ADAPTOR PROTEIN
PRINCIPALLIGANDS
TLR1/TLR2 (dimer)
Surface
MyD88,TI-RAP and TRAM
Bacterial cell-wall components
TLR1/TLR6 (dimer)
TLR4 LPS
TLR5MyD88
Flagellin
TRL10 Unknow
TLR3
Endosome
TRIF dsRNA
TLR7 ssRNA
TLR8
TLR9 CpG DNA
TLR13 23S rRNA
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TLR2
Canonicalinflammasomes
Non-canonicalinflammasome
MyD88
TLR2
TRAM
pro-IL-1β
pro-IL-18
IL-1β
IL-18
IL-1β
IL-18
pro-IL-1β
pro-IL-18
TLR1/6
Bacterial cell wall components
IL-18
IL-1β
IL-18
Pyroptosis
Pro-Casp-11 Caspase-11
CytosolicLPS
NLRP3Pro-Casp-1
ASC
Caspase-1
Danger signals (e.g. ATP) Crystalline substances (e.g. alum, uric acid) Microbial toxins (e.g. nigericin)
Pyroptosis
TLR13
23SrRNA
IRF3
IRF3IRF3
ISRE3
IFN-β Pro-inflammatory cytokinesPro-inflammatory cytokines
MyD88
AP-1
MKKs
ERK JNK p38
Junc-fos
IKKεTBK1DDX3
NLRP3Pro-Casp-1
ASC AIM2Pro-Casp-1
ASC
dsDNA
Caspase-1
IL-1β
TLR & NLR Signaling Pathways
NLRP1Pro-Casp-1
ASCNLRC4
Pro-Casp-1ASC NAIPs
Flagellin
MDP, Anthrax toxin
MyD88
TLR
PAMPs
IKKβ
IκB
p50 p65
p50 p65
NEMO
RIP2
NOD1NOD2
iE-DAPMDP
NF-кB
Pro-inflammatory cytokines
AP-1
MKKs
ERK JNK p38
Junc-fos
CARD9TAB2 TAB3
TAK1
IRAK1 IRAK2IRAK4
Bcl-10
MALT1
Pellino
TIRAPMyD88
TLR6TLR2TLR1
MyD88
TRAM
TLR8TLR3
TLR7TLR9
TLR4ssRNA
dsRNAssRNA
CpGDNA
Endosome
TRAF6
TIRAPMyD88
LBP
TLR4
MD2
CD14
LPS
IKKβ
IκB
p50 p65
p50 p65
NEMO
NF-кB
TRIF
MyD88
TLR5
Flagellin
IRAK1 IRAK2
TRAF6
IRAK4
TRAF6
TRAF3TANK NAP1
RIP1TRADD
IRAK4
IKKβ
IκB
p50 p65
p50 p65
NEMO
NF-кB
IKKα IKKα IKKα IKKα
IRF7
IRF7IRF7
ISRE7
IFN-α
Bacterial cell wall components
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Dec�n-1
P P
P
P
P
P
Apoptose
DHX29PKR
NEMO
IKKβIKKα
IкBp50 p65
Ub
ZDHHC1
LSP1
IKKε
CYLD
Bcl3
Bcl3
An�-inflammatory cytokines
NF-кB
Fucose
DC-SIGN
CNK
KSR1
Raf-1
LSP1
Raf-1
p65
STING
cGAMPc-di-GMPc-di-AMPcGAMP
p65
IKKβIKKα
ISRE7
Type I IFNs IFN-l1 IFN-βIL-2
NF-кB
Pro-inflammatory cytokines
Caspase 8
FADD
DAI
DDX41
TRAF6
TBK1
Pro-Casp-1ASC
Caspase-1
AIM2
pro-IL-1β IL-1β
IFI16cGAS
MRE11
MyD88
IRF1IRF3/7 IRF3/7
ISRE1/7
p50 p65
DHX15
DDX3
IKKεTBK1
IRF3/7
IRF7 IRF7 IRF7
IFN-α
ISRE3/7
Pro-inflammatory cytokines
CLR, RLR & CDS Signaling Pathways
IкBp50 p65
p50 p65 Junc-fos
Pro-inflammatory cytokines
NF-кBNFAT
FcRγ
SykFcRγ
Syk
TBK1
IRF3
IRF3 IRF3
ISRE3
c-di-GMPc-di-AMP
AP1
dsRNA
IPS1
MDA-5 RIG-I
LRRFIP1
Ku70
DHX36
IFIX
dsDNA
β-catenin
Pathogen dsDNA Host dsDNA
LGP2
Mitochondrion
Endoplasmic re�culum
DHX9
High mannose
Dec�n-2
NEMO
IKKβIKKα
ERK JNK p38
PLCγ
IP3DAG
RNA Virus
Calcineurin
NFAT
CARD9
MALT1Bcl-10
Ca2+PKCδ
β-Glucan
Syk
DC-SIGN
MAPKs
Mincle
α-Mannose, cord factor
High mannose, α-mannan
NF-кB
RNAPol III
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TLR-NLR PATHWAYS
CLR-RLR-CDS PATHWAYS
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NOD-LIKE RECEPTORS (NLRS)
NLRs constitute a family of intracellular pattern recognition
receptors (PRRs) that contains more than 20 members in mammals.
Although the ligands and functions of many of these receptors are
not known, their primary role is to recognize cytoplasmic pathogen-
associated molecular patterns (PAMPs) and/or DAMPs, inducing
immune responses.
NLRs are characterized by a tripartite-domain organization with
a conserved nucleotide binding oligomerization domain (NACHT/
NOD), leucine-rich repeats (LRRs) involved in microbial sensing and
one of four N-terminal effector domains.
NLRs are classified in to four sub-families, which are named
according to the N-terminal effector domain: NLRA (Acidic
transactivation domain), NLRB (Baculovirus inhibitor repeat
domain), NLRC (Caspase recruitment domain) and NLRP (Pyrin
domain). There is also a sub-family known as NLRX, whose
members do not contain an effector domain analogous to those
mentioned above.
RIG-I-LIKE RECEPTORS (RLRS) AND CYTOSOLIC DNA SENSORS (CDS)
RLRs are a family of cytoplasmic RNA helicases that are critical for
host anti-viral responses. The RLRs include the RNA sensors RIG-I
and MDA-5, which, upon activation, drive transcription factors that
control the transcription of genes encoding interferons and other
cytokines.
RIG-I and MDA-5 sense double-stranded RNA, a replication inter-
mediate for RNA viruses. Upon binding of specific types of dsRNA,
each of these sensors activates the mitochondrial-bound adaptor
protein MAVS, which leads to production of type I interferons. The
cytosolic protein LGP2, which contains a RNA-binding domain, acts
as a negative feedback regulator of both RIG-I and MDA-5.
Recent advances in the recognition of nucleic acids have identified
several CDSs, which detect double-stranded DNA (dsDNA) of
pathogen, self or tumor origin, leading to the induction of inter-
ferons and/or the processing of pro-inflammatory cytokines. The
best-known CDSs are cGAS, AIM2 and IFI16.
Upon detection of dsDNA and DNA/RNA hybrids, cGAS produces
the cyclic dinucleotide 2’3’-cGAMP, which is the endogenous ligand
of the adaptor protein STING. Once activated, STING induces type
I IFNs and pro-inflammatory cytokines through the IRF3 and NF-
kB pathways, respectively.
AIM2 is unique among CDSs in that it forms an inflammasome (see
“Inflammasomes” section, below), which, like other inflammasomes,
contains the accessory proteins ASC and Pro-Casp-1.
Unlike other CDSs, IFI16 shuttles between the cytoplasm and the
nucleus.
Other noteworthy CDSs include DAI, DDX41, IFIX and LRRFIP1.
C-TYPE LECTIN RECEPTORS (CLRS)
CLRs, also called the C-type lectin receptors encompass a large
family of phagocytic receptor proteins that bind to carbohydrate
moieties of various pathogens. The importance of CLRs in shaping
the adaptive immune response is becoming increasingly apparent.
The lectin activity of CLRs is mediated by conserved carbohy-
drate-recognition domains (CRDs). These receptors are involved in
fungal recognition and in modulation of innate immune mechanisms
for pathogen clearance or for antigen presentation to T lympho-
cytes.
The principal human CLRs are the surface receptors DC-SIGN,
Dectin-1, Dectin-2 and Mincle, and the soluble receptor man-
nose-binding lectin (MBL).
PRODUCT DESCRIPTION UNIT SIZE
NLRAAcidic transactivation
(A)CIITA
NLRBBaculovirus inhibitor repeat
(BIR)NAIP
NLRCCARD
(Caspase recruitment domain)NOD1/2, NLRC 3/4
NLRP Pyrin NLRP1, NLRP3
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INFLAMMASOMES
Inflammasomes are caspase-1-activating protein complexes
assembled by certain NLRs. Caspase-1 is activated by
inflammasomes through autoproteolytic maturation, leading to
processing and secretion of the pro-inflammatory cytokines IL-1b
and IL-18.
Four inflammasomes have been identified to date. These include
three inflammasomes defined by their constituent NLR protein:
the NLRP1 (or NALP1b) inflammasome, the NLRC4 (or IPAF)
inflammasome and the NLRP3 (or NALP3) inflammasome. There
is also an inflammasome built around the DNA sensor AIM2, a
member of the IFI16 family.
Inflammasomes fulfill a central role in innate immunity by detecting
and responding to specific DAMPS and PAMPS, see table.
AUTOPHAGY AND INNATE IMMUNITY
Autophagy is a mechanism that cells use to sequester, remove and
recycle waste. In autophagy, macromolecules in the cytosol are
engulfed in a newly formed phagocytic body and subsequently
digested in a lysosome that releases the resultant metabolites back
into the cytosol.
Autophagy, often referred to as macroautophagy, serves to recycle
large chunks of cytoplasm as a source of nutrients, which enables
cells to maintain macromolecular synthesis and energy homeosta-
sis during starvation and other stressful conditions.
Moreover, cells use autophagy to regulate the activity of specific
signaling proteins, to prevent accumulation of damaged organelles
or long-lived, aggregate-prone proteins, and to remove incom-
ing threats such as intracellular pathogens. Thus, autophagy has
emerged as a critical component of innate immunity.
The interplay between autophagy, PRRs and inflammation is highly
complex and encompasses several regulatory mechanisms that
ensure balanced innate immune responses.
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PRODUCT DESCRIPTION
AIM2 dsDNA
NLRC4 Flagellin
NLRP1 MPD, anthrax, toxin
NLRP3ATP, uric, acid, alum, nigericin,
oxidized mtDNA, bacterial RNA
PRR & INNATE IMMUNITY - INVIVOGEN.COM
PRRS FAMILIES
Toll-Like Receptors - TLRs Best characterized receptors involved in early innate immune response to invading pathogens
NOD-Like Receptors - NLRs Intracellular pattern recognition receptors that recognize cytoplasmic pathogen-associated molecu-lar patterns
RIG-I-Like Receptors - RLRs Cytoplasmic RNA helicases that are critical for host antiviral responses
C-type Lectin Receptors - CLRs Receptors involved in fungal recognition and modulation of the innate immune response
Cytosolic DNA Sensors & STING Receptors to diverse molecules of microbial origin (PAMPs), or released from damaged or dying cells (DAMPs)
Inflammasome Large intracellular multiprotein complexes that play a central role in innate immunity
TOOLS FOR PRRS STUDY
PRR & PAMP Detection Rapid, convenient and reliable detection of pattern recognition receptors and pathogen-associated molecular patterns