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298 Part IV: Molecular and Cellular Hematology Chapter 20: Innate Immunity 299

A total of five TIR adapter proteins are encoded in the human (JNK), and p38 kinases. These kinases trigger the activation of other tran-
genome. These adapters are MyD88 (myeloid differentiation primary scription factors, including c-Jun, which together with c-Fos forms the
response 88), MAL (MyD88 adaptor-like; also known as TIRAP), transcription factor AP1, and members of the cyclic adenosine mono-
TRIF (Toll/interleukin-1 receptor domain-containing adaptor inducing phosphate (AMP) response element-binding protein (CREB) family.
IFN-β; also known as TICAM1 and first identified by a mutant allele The TRIF-dependent TLR signaling pathway is activated by TLR3
known as Lps2), TRAM (TRIF-related adaptor molecule; also known and TLR4, and results in the induction of type I IFNs as well as inflam-
as TICAM2), and SARM (sterile-α and armadillo motif). The function matory response genes (see Fig. 20–3). Upon receptor activation, TRIF
of SARM remains unknown, and it is the most distantly related par- interacts with TRAF3, which recruits TANK-binding kinase 1 (TBK1)
alog among the adaptors. However, the four remaining adapters have and IKKε (both distantly homologous to the IKKs). 52,53 This complex
well-defined roles in signal transduction. All four of these adapters are engages and phosphorylates interferon response factor (IRF) 3, an
required for normal signaling from the LPS receptor, TLR4; MyD88 and interaction that may be mediated by phosphatidylinositol-5-phosphate
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MAL act in concert with one another, and TRIF and TRAM act together, generated by PIKfyve. IRF3 dimerizes and translocates to the nucleus
so that two primary branches of the LPS signaling pathway diverge at to activate transcription of type I IFN genes with the aid of deformed
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the level of the receptor. 41,42 In contrast, TRIF alone serves TLR3 signal- epidermal autoregulatory factor-1 (DEAF-1). Two other IRF proteins,
ing; MyD88 and MAL (but neither TRIF nor TRAM) serve TLR2; and IRF1 and IRF7, also activate type I IFN genes, but in response to sig-
MyD88 alone serves TLRs 7, 8, and 9. Mutational inactivation of MyD88 naling from TLR7 and TLR9 particularly in plasmacytoid dendritic
creates a severe immunodeficiency state in mice and humans, 43,44 and cells. 56,57 Activation of IRF3 and IRF1 can initiate expression of the IFN-
compound homozygosity for mutations affecting both MyD88 and TRIF β gene. 58,59 IFN-β mediates antiviral effects, and is also required for the
causes immunodeficiency that is still more severe, in which animals are upregulation of costimulatory proteins (e.g., CD40, CD80, and CD86)
essentially unable to sense the presence of most microbes. 42 that enhance the activation of an adaptive immune response. Hence, the
Two main branches of signaling, dependent on MyD88 or TRIF, adjuvant effects of LPS and dsRNA are dependent upon the type I IFN
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mediate the effects of TLR activation in conventional dendritic cells, receptor. IRF7 induces the expression of the IFNα genes. 59,61 Both α and
macrophages, and fibroblasts (see Fig. 20–3). The MyD88-depen- β IFNs bind to the type I IFN receptor rendering similar if not identical
dent pathway is used by all TLRs except TLR3, as mentioned above. biological responses.
MyD88 is believed to assemble into a helical complex called the Myd- To induce inflammatory response genes, TRIF recruits receptor-in-
dosome upon receptor activation, engaging the serine kinases IRAK teracting protein (RIP) 1 following its polyubiquitination by the E3 ligase
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(interleukin-1 receptor-associated kinase) 4 and IRAK2 or IRAK1 Pellino. RIP1 interacts with the TRAF6/TAK-1 complex leading to
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through death domain interactions. Signaling proceeds via phospho- NF-κB activation following the pathway described above for MyD88-de-
rylation of IRAK2 or IRAK1 by IRAK4. No comparable structural data pendent signaling. For reasons that remain unclear, the heteromeric
illuminate the function of MAL, TRIF, or TRAM proteins, but it is clear MyD88/MAL complex is incapable of driving type I IFN gene expression.
that TRIF can directly engage TLR3. The activated Myddosome recruits
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the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor-associated Countervailing Influences in Toll/Interleukin-1 Receptor
factor (TRAF) 6, a cellular scaffold protein that coordinates the recruit- Adapter Signaling
ment of several other protein kinases. MyD88 also interacts with TRAF3; IRAK-M, a homologue of IRAKs 1, 2, and 4, is an inhibitor of TIR
however, degradative K48-linked ubiquitination of TRAF3 by cIAP1/2 domain signaling and may participate in feedback inhibition of signal-
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during MyD88-dependent TLR signaling is necessary for the activa- ing known as “endotoxin tolerance.” In addition, suppressor of cytok-
tion of mitogen-activated protein kinases (MAPKs) and production of ine signaling 1 (SOCS-1) inhibits signal transduction from the Janus
inflammatory cytokines. In conjunction with the E2 ubiquitin-conju- kinase (JAK)/signal transducer and activator of transcription (STAT)
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gating enzyme 13 (Ubc13) and the Ubc-like protein Uev1a, TRAF6 adds pathway (Chap. 17) activated by type I IFN, one of the key cytokines
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chains of K63-linked polyubiquitin to itself, as well as inhibitor of κB elicited in the course of an innate immune response. A20 and CYLD,
(IκB) kinase γ (IKKγ; also called NEMO [NF-κB essential modulator]) both deubiquitination enzymes, remove the K63 ubiquitin tails from
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and to TRAF2 (reviewed in Ref. 48). Transforming growth factor-β– TRAF6, NEMO, and RIP, inhibiting the activation cascade. Still more
activating kinase 1 (TAK-1) forms a complex with TAB1, TAB2, and distally, inhibition of signaling via antiinflammatory cytokines (such as
TAB3, is recruited to the TRAF6 complex, and phosphorylates IKKβ, IL-10 or transforming growth factor [TGF]-β) acts to limit responses
which in complex with IKKα and IKKγ phosphorylates IκB (an inhib- initiated by the TLRs.
itor of the p65 form of NF-κB), leading to its K48-ubiquitin–mediated
degradation. Nuclear translocation of homo- or heterodimers com- SENSORS OF THE NUCLEOTIDE-BINDING
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posed of p65 and/or p50 NF-κB ensues. NF-κB drives the transcription OLIGOMERIZATION DOMAIN-LIKE
of hundreds of genes encoding proteins that form the inflammatory
response. Mitochondrial reactive oxygen species (ROS) are also pro- RECEPTOR FAMILY
duced in macrophages as a result of TLR4, TLR2, and TLR1 activation; An extensive family of proteins defined by their motif structure has
this antibacterial response depends on the translocation of TRAF6 to recently been recognized for its participation in innate immune
mitochondria to engage and ubiquitinate a protein called ECSIT, which responses to intracellular microbes as well as noninfectious inflam-
functions in mitochondrial respiratory chain assembly. 49 matory stimuli, including, for example, uric acid crystals and alumi-
At the same time, the IKK complex activated by TAK-1 phospho- num hydroxide particles. Collectively called the nucleotide-binding
rylates the p105 form of NF-κB and MAP3K8 (also known as Tpl2), oligomerization domain (NOD)-like receptors (NLRs), the proteins
proteins that form a complex in which MAP3K8 is inactive under basal contain CARD (caspase activating and recruitment domain), Pyrin,
conditions. This leads to the degradation of p105 NF-κB, and to the acti- or BIR (baculovirus inhibitor of apoptosis repeat) domains followed
vation of MAP3K8. 50,51 MAP3K8 phosphorylates and activates MEK1 by nucleotide-binding NACHT domains and LRR domains arranged
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and MEK2, while independently MEK3 and MEK6 are activated by in tandem, and have been assigned to several subfamilies (Fig. 20–4).
TAK-1. The MEKs activate MAPK family members, including extracel- Mutations within different representatives of the family produce dom-
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lular signal-regulated kinase (ERK) 1 and ERK2, c-Jun N-terminal kinase inant or semidominant inflammatory diseases. In some cases there is

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