CARD9 Signaling in the Innate Immune Response

CARD9 Signaling in the InnateImmune Response

Jurgen Ruland

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen,Munich, Germany

CARD9 is a caspase recruitment domain-containing signaling protein that is highlyexpressed in dendritic cells and in macrophages. Work over the last two years has iden-tified CARD9 as a central regulator of innate immunity. Best characterized is CARD9’sfunction downstream of ITAM-bearing or ITAM-coupled receptors in myeloid cells, in-cluding its essential role downstream of the antifungal pattern-recognition receptorDectin-1. In the ITAM receptor pathway, CARD9 couples receptor proximal splenic ty-rosine kinase SYK activation to the canonical NF-κB pathway. In addition, CARD9 isinvolved in the activation of p38 and JNK kinases and it can function downstream ofcytosolic pattern-recognition receptors. CARD9 signaling mediates mammalian innateimmune responses against selected fungi, bacteria, and viruses and can prime andshape adaptive immunity. This review will summarize current knowledge on CARD9signaling and its function in the innate immune response.

Key words: CARD9; signaling; innate immunity

Introduction

The innate immune system senses microor-ganisms through germline-encoded pattern-recognition receptors (PRRs) that bind con-served and invariant structures on microbes,termed pathogen-associated molecular pat-terns (PAMPs).1 These PAMPs, such as bac-terial and fungal cell wall components andviral nucleic acids, are unique to microbesand distinguish them from the host. Severalclasses of PRRs are known that recognize dis-tinct microbial products. The PRRs include thetransmembrane Toll-like receptors and C-typelectins as well as cytosolic nucleotide-bindingoligomerization domain (NOD) proteins andsensors of viral nucleic acids like retinoicacid inducible gene (RIG)-I and melanomadifferentiation-associated protein 5 (Mda5) he-licases. To fine-tune immunity, individual PRRs

Address for correspondence: Jurgen Ruland, III. Medizinische Klinik,Klinikum rechts der Isar, Technische Universitat Munchen, IsmaningerStr. 22, 81675 Munich, Germany. [email protected]

trigger distinct but interrelated intracellularsignaling pathways that collaborate for op-timal cell activation. Central for the inte-gration of signals downstream of PRRs areadaptor and scaffold proteins that relayreceptor-proximal events to core transcriptionfactors. One recently recognized adapter pro-tein with an emerging role in the innate im-mune response is CARD9.

Identification of CARD9

CARD9 was originally identified through adatabase search for caspase recruitment do-main (CARD)-containing proteins.2 CARDsare homophilic protein–protein interactionmodules that mediate binding between CARD-containing molecules. The CARD9 proteinhas a bipartite structure. In addition to its N-terminal CARD, it contains a coiled-coil re-gion at the C-terminus that mediates proteinoligomerization (Fig. 1A). CARD9 is expressedin a variety of tissues including spleen, liver,placenta, lung, peripheral blood, brain, bone

Ann. N.Y. Acad. Sci. 1143: 35–44 (2008). C© 2008 New York Academy of Sciences.doi: 10.1196/annals.1443.024 35

36 Annals of the New York Academy of Sciences

Figure 1. Structural features of CARD9 and related or associated signaling proteins.(A) CARD9 contains a caspase recruitment domain (CARD) and a coiled coil domain. (B)Members of the CARMA (CARD MAGUK) family of proteins are CARD9 relatives. In additionto the CARD and coiled coil domain, they process a MAGUK region composed of a PDZ, aSH3, and a GUK domain that can link CARMAs to the plasma membrane. (C) The effectormolecules BCL10 and MALT1. BCL10 contains a CARD that can interact with the CARD ofCARD9. In addition, BCL10 possesses a serine and threonine (S/T)-rich region that playsa negative regulatory role in signal transduction. The paracapsase MALT1 is composedof a Death Domain (DD) and immunoglobulin repeats (Ig) that mediate protein—proteininteractions and contains in addition a proteolyticly active domain that resembles the catalyticregion of Caspases (Casp-like).

marrow, and fetal liver2 with highest expressionin myeloid cells particularly in macrophagesand in dendritic cells.3 Structurally, CARD9is related to the scaffold proteins of theCARMA (CARD MAGUK) family, which areCARMA1 (CARD11), CARMA2 (CARD10),and CARMA3 (CARD14)4,5 (Fig. 1B). In con-trast to the CARMAs, the CARD9 proteinlacks the C-terminal MAGUK (membrane-associated guanylate kinase) region contain-ing a PDZ, an Src Homology 3 (SH3), anda Guanylate Kinase (GUK) domain that medi-ates association of CARMA proteins with theplasma membrane.6

Initial mammalian two-hybrid studies havedemonstrated that the CARD of CARD9 candirectly interact with the CARD of BCL10(Fig. 1C).2 The adapter protein B-Cell Lym-phoma 10 (BCL10) is well known for its func-tion in lymphocytes.7 BCL10 cooperates di-rectly with CARMA1 and the paracaspaseMALT1 (Fig. 1C) to form a trimolecular com-plex in membrane-associated lipid rafts that

relays antigen receptor–proximal events tothe transcription factor NF-κB and to the c-Jun N-Terminal Kinase (JNK) and p38 ki-nase cascades for the activation of adaptive Tand B cell immune responses.7 CARD9, likeCARMA1 can engage BCL10/MALT1 signal-ing but instead operates selectively in myeloidcells. Three groups have independently gener-ated CARD9-deficient mice and have recentlyuncovered essential roles for CARD9 in thecontrol of innate immunity.3,8,9

CARD9 Is a Central Regulatorof Dectin-1 Signaling

Gross and colleagues and Hara and col-leagues recognized a positive regulatory func-tion for CARD9 downstream of the β-glucanreceptor Dectin-1 both in dendritic cells andin macrophages.8,9 Dectin-1 is the prototype ofsignaling C-type lectin receptors that containan atypical immunoreceptor tyrosine-based

Ruland: CARD9 in Innate Immunity 37

Figure 2. CARD9 couples Dectin-1 signaling to the NF-κB pathway. Ligation of theβ-glucan receptor Dectin-1 induces SYK activation to mediate phagocytotic and pro-inflammatory responses. CARD9 operates downstream of SYK and cooperates with BCL10and MALT1 to specifically transduce Dectin-1 signals to the canonical NF-κB pathway for pro-inflammatory responses. In addition, CARD9/BCL10/MALT1 controls JNK and p38 kinaseactivation.

activation motif (ITAM) in their intracellulartail that is related to the classical ITAMs oflymphocyte antigen receptors, Fc receptors, ornatural killer (NK) cell receptors.10 In contrastto the tandem tyrosines that are present in stan-dard ITAMs, Dectin-1 contains only a single“YxxL” motif that is both necessary and suffi-cient for signal transduction. The ectodomainof Dectin-1 can recognize β1-3 and β1-6 linkedβ-glucans, which are highly enriched in thecomplex fungal cell wall preparation Zymosan.These β-glucans are fungal PAMPs11 that canelicit potent pro-inflammatory responses.12,13

Pure β-glucan preparations like Curdlan fromthe bacterium Alcaligenes faecalis14 can also serveas Dectin-1 agonists.15 β-glucan binding toDectin-1 leads to a phosphorylation of thekey tyrosine in the Dectin-1 ITAM by sar-coma (Scr) kinases. These events initiate a di-

rect recruitment of the SH2-domain contain-ing tyrosine kinase SYK to Dectin-1, result-ing in SYK activation. Activated SYK controlsDectin-1-dependent phagocytosis, and signalsfor the production of cytokines and chemokinesand for the activation of antigen presentingcells.15,16 CARD9 was shown to operate down-stream of SYK and to specifically control SYK-dependent activation of gene transcription butnot SYK-dependent phagocytosis (see Fig. 2).Consistently, CARD9-deficient myeloid cellsare defective in Zymosan- or Curdlan-inducedcytokine production or upregulation of cos-timulatory molecules but are regularly able tophagocytose fungal particles.8,9,15

Although it is unclear how SYK couplesto CARD9, first biochemical and genetic ex-periments demonstrated that CARD9 utilizesBCL10 and MALT1 to mediate Dectin-1


signaling for the activation of the transcriptionfactor NF-κB and for the control of the JNKand p38 MAPK pathways (Fig. 2).8,9 Consis-tently, DCs or macrophages deficient for eitherBCL10 or MALT1 show, similar to CARD9-deficient cells, severe defects in Zymosan-induced NF-κB activation and cytokineproduction. The molecular role of CARD9downstream of Dectin-1 is thus comparableto the well-characterized role of CARMA1 inlymphocytes, namely linking tyrosine kinase-dependent receptor proximal signals to theBCL10/MALT1 complex for canonical NF-κB control and activation of JNK and p38.How the CARD9/BCL10/MALT1 moduleengages these downstream pathways is notwell defined. However, based on the similar-ity between antigen receptor signaling and theDectin-1 pathway, it is conceivable that furthereffector molecules could be conserved betweenthe two systems. CARD9/BCL10/MALT1downstream signaling in myeloid cells mighttherefore involve TNF Receptor AssociatedFactor (TRAF) proteins like TRAF2 andTRAF6 as well as ubiquitin modifiers includingUbiquitin-Conjugating Enzyme 13 (UBC13)-Ubiquitin-Conjugating Enzyme E2 Variant 1A(UEV1A), TAK1-Binding Protein (TAB) pro-teins, and the kinase Transforming-Growth-Factor-Beta-Activated Kinase 1 (TAK1).

The innate CARD9/BCL10/MALT1 cas-cade is a key for mammalian antifungalimmunity. Experiments using CARD9−/−,BCL10−/−, and MALT1−/− myeloid cells havedemonstrated that each individual protein isessential for cytokine production upon stim-ulation with whole Candida albicans cells in

vitro. Moreover, specific Candida albicans infec-tion experiments with CARD9-deficient micehave shown that these animals are completelyunable to clear the fungus.9 Although theCARD9−/− animals were not directly com-pared to Dectin-1 knockout mice, the literaturesuggests that CARD9−/− mice are much moresusceptible to Candida albicans infection thanDectin-1−/− mice.12,13 Thus, additional fun-gal recognition receptors distinct from Dectin-1

are likely to signal via CARD9 for mammalianhost defense.

CARD9 Couples Multiple MyeloidITAM-Bearing or ITAM-Coupled

Receptors to NF-κB

Myeloid cells express in addition to Dectin-1 multiple other receptors that contain ITAMmotifs in their intracellular tails or that cou-ple to the ITAM-containing signaling chainsDNAX-Activating Protein of 12 kDa (DAP12)or FcRγ.17 Hara and colleagues hypothesizedthat such ITAM receptors could, similar toDectin-1, also activate cells via CARD9.8 In-deed, CARD9-deficient bone marrow-derivedDCs or macrophages stimulated through theFcRγ-coupled FcγRIII receptor (CD16) areimpaired in tumor necrosis factor (TNF)-α,interleukin (IL)-6, or IL-12 production. More-over, CARD9 was found to control cy-tokine production in response to triggeringof osteoclast-associated receptor (OSCAR),which is a dendritic cell-activating receptorthat associates with FcRγ,18 or upon ligationof triggering receptor expressed on myeloidcells 1 (TREM-1)19 or myeloid-associatedimmunoglobulin-like receptor II (MAIR II),20

two cell surface receptors that are DAP-12-associated. Consistent with the model thatCARD9 uses BCL10 for NF-κB activation,the engagement of DAP-12 or FcRγ signal-ing failed to induce degradation of the In-hibitor kappa of B alpha (IκBα) inhibitoryprotein or NF-κB DNA binding in the ab-sence of either CARD9 or BCL10. Thus, alltested ITAM signals in dendritic cells andin macrophages utilize CARD9–BCL10 com-plexes to engage NF-κB for innate immunecell activation (Fig. 3). Whether they all requireMALT1 remains to be determined. Yet, theseresults collectively indicate—together with theknown role of CARMA1/BCL10 complexesdownstream of antigen receptors, activatingNK cell receptors and the FcεRI on mastcells21–24—a general principle that potentially


Figure 3. CARD9 transduces signals from multiple ITAM-coupled receptors to the NF-κBpathway. Various receptors on dendritic cells and on macrophages, including TREM-1, MAIR-II, FcγRIII, and OSCAR, that are coupled to ITAM-containing signaling chains DAP-12 or FcRγ

engage the CARD9/BCL10 module for NF-κB activation and subsequent cytokine production.

all ITAM-coupled immune receptors use ei-ther the CARD-coiled-coil protein CARD9 orCARMA1 to engage BCL10-mediated NF-κBactivation in a cell type- or receptor-specificmanner.

Function of CARD9 Downstreamof Intracellular Sensors

The recognition of intracellular microbialproducts by the innate immune system de-pends on cytoplasmic PRRs. The NOD familymembers contain a C-terminal leucine-richrepeat (LRR) domain for ligand recogni-tion, a central nucleotide binding NACHTdomain, and at least one N-terminal CARDthat mediates CARD–CARD interactions withother proteins.25 NOD1 and NOD2 stimu-lation via peptidoglycan from bacterial cellwalls or its cytoplasmic breakdown products

leading to NACHT domain-mediated homo-oligomerization of the proteins, and a recruit-ment of CARD molecules for cell activation.Both NOD1 and NOD2 interact with theCARD kinase RIP2 (or RICK) to signal toNF-κB and in addition activate the MAP ki-nases p38 and JNK. Recent work has im-plicated CARD9 in the selective control ofNOD2-dependent p38 and JNK signaling3

(Fig. 4).The activating ligand for NOD2 is muramyl

dipeptide (MDP), a conserved structure withinthe bacterial PAMP peptidoglycan.25 Hsu andcolleagues observed defective TNF-α and IL-6production in CARD9−/− macrophages stim-ulated with MDP, whereas the responses todefined Toll-like receptor (TLR) ligands wereintact.3 Although, CARD9−/− macrophagesdisplay normal NF-κB induction after MDPtreatment, they exhibited selective defects inp38 and JNK signaling, suggesting a restricted


Figure 4. The intracellular pattern-recognition receptor NOD2 is responsible for the detec-tion of bacterial muramyl dipeptide within peptidoglycan. Ligand binding via the leucine-richrepeat domain (LRR) induces downstream signaling. Whereas the CARD-containing kinaseRIP2 or RICK transduces the signal to NF-κB, CARD9 is implicated in NOD2-induced p38 andJNK activation.

and specific role for CARD9 in NOD2 sig-nal transduction. Further evidence for aninvolvement of CARD9 in NOD2 responseswas obtained from overexpression studies re-vealing that CARD9 can form trimolecularcomplexes with NOD2 and RIP2 (RICK). Theco-overexpression of CARD9 and NOD2 acti-vates p38 and JNK synergistically, an effect thatis further enhanceable by MDP stimulation.CARD9 thus operates downstream of NOD2and segregates RIP2-dependent NF-κB induc-tion from JNK and p38 MAPK activation (fora model see Fig. 4).

CARD9−/− macrophages were also infectedwith the intracellular bacterium Listeria mono-

cytogenes,3 revealing again specific CARD9-dependent p38 and JNK activation butCARD9-independent NF-κB control. More-over, in vivo production of IL-6 and TNF-αwas reduced in Listeria monocytogenes infectedCARD9−/− mice and the animals were im-paired in Listeria monocytogenes clearance.3,8

Thus, CARD9 signaling can contribute to theinnate immune response against certain intra-cellular bacteria in vitro and in vivo, presumablydue to a functional role downstream of the in-tracellular receptor NOD2.

Intracellular PRRs, particularly receptorsof the helicase family and certain TLRs like

TLR3 and TLR7, are also involved in therecognition of viruses and viral nucleic acids.26

For a first investigation of CARD9’s func-tion in viral recognition signaling, CARD9−/−

macrophages were stimulated with poly(I:C) asa functional mimic of double stranded RNAviruses, revealing selective roles for CARD9in poly(I:C)-induced JNK and p38 activation.3

Moreover, CARD9-deficient cells exhibit de-fective JNK and p38 activation and cytokineproduction after infection with the RNA virusesvesiculo-stomatitis virus or lentivirus. Still, theexact viral biosensors that engage CARD9upon nucleic acid binding remain to be iden-tified and the role of this pathway in immuneresponses to viruses in vivo is still unclear.

Modulation and Regulation of TLRSignaling via CARD9

Complete microbes do not only contain lig-ands for a single PRR but complex compo-sitions of PAMPs that stimulate different PRRsystems simultaneously. Collaborative signalingfrom different PRRs induces cellular responsesthat are higher or qualitatively different froman individual response to a single PRR lig-and.27 CARD9 signaling can collaborate with


Figure 5. CARD9 signaling can cooperate with TLR/MyD88 signaling for optimal innateimmune cell activation. Simultaneous triggering of CARD9 (Signal A) and TLR/MyD88 (SignalB) pathways, for example via ITAM receptor ligation and TLR coligation, induces innateimmune responses that are quantitatively and potentially also qualitatively distinct from singleTLR or CARD9 signals.

TLR signaling to enhance TLR-induced cellactivation (for a model see Fig. 5). This co-operative effect was demonstrated by costimu-lating CARD9-deficient myeloid cells throughthe ITAM-coupled receptor TREM-1 (corre-sponding to signal A in Fig. 5) together withseveral individual TLR ligands (correspondingto signal B in Fig. 5).8 The TLR ligands usedin these experiments included LPS for TLR4,Pam3CSK4 for TLR2, and CpG DNA forTLR9, which all by themselves activate classi-cal Myeloid Differentiation Primary ResponseGene (88) (MyD88)-dependent signaling. Inwild-type cells, TLR-induced cytokine produc-tion was substantially enhanced by TREM-1costimulation. However CARD9−/− DCs didnot show TREM-1-induced enhancement,demonstrating functions for CARD9 in cooper-ative TLR activation. CARD9 can presumablyalso orchestrate the collaboration of innate sig-nals in other settings including infections in vivo,but this remains to be tested.

The specific role of CARD9 directly down-stream of TLR ligation without costimulation is

not finally resolved. Both Gross and colleaguesand Hsu and colleagues detected regular cy-tokine production in CARD9−/− dendritic cellsor macrophages upon stimulation with the pureTLR ligands LPS, Pam3CSK, or diacetylatedlipopeptide FSL-1 (both for TLR2) or withCpG, indicating CARD9-independent TLRsignaling.3,9 In contrast, Hara and colleaguesreported impaired TNF-α or IL-6 productionupon stimulation with LPS, Pam3CSK, andCpG specifically in CARD9−/− DCs but notin macrophages. Since all three groups usedsimilar gene targeting strategies for CARD9

gene disruption and they all utilized mice ina mixed 129J/C56Bl6 background, the rea-sons for these seemingly discrepant findingsare unclear. One possibility that could explaindifferent TLR responses is different cultureconditions—for example undefined CARD9-activating ligands in the serum—that could orcould not costimulate or pre-activate dendriticcells in a CARD9-dependent manner, result-ing in a modulation of the subsequent TLRresponses.


Innate CARD9 Signaling Activatesand Shapes Adaptive Immune

Responses

One important feature of PRR signaling inantigen presenting cells (APCs) is the activa-tion and the “instruction” of adaptive immu-nity.28 APCs can decode different classes ofpathogens via their distinct PRRs and theireffector pathways. The cells then generatea milieu of cytokines and costimulatory fac-tors that direct the activation and differenti-ation of naıve lymphocytes in a manner thatis tailored for defense against the invadingpathogen. Stimulation of CARD9 signaling inDCs via selective Dectin-1 ligands induces thematuration of DCs into full effector APCs.Such cells can prime naıve T cells in vitro

and induce proliferation and differentiation ofCD4+ T helper cells. Dectin-1 ligation causescomparable to TLR/MyD88 triggering a po-tent upregulation of the costimulatory cell sur-face molecules CD40, CD80, and CD86. Yet,the combination of DC cytokines that is pro-duced upon Dectin-1/CARD9 signaling differsprofoundly from the cytokine profile inducedby classical TLR/MyD88 activators, as theDectin-1/CARD9 pathway induces consider-able amounts of IL-2, IL-6, IL-10, TNF-α, andIL-23, but little IL-12.15 This differential cellactivation effect has functional consequencesfor subsequent T cell differentiation. WhereasTLR-stimulated DCs direct mainly Th1 T cellresponses, Dectin-1/CARD9 activation in DCsinstructs both the differentiation of IFN-γ-producing Th1 cells and the generation of IL-17-producing Th17 cells. In the context of anti-fungal immunity this could be important, sinceIL-17 has been linked to resistance against Can-

dida albicans29 and CARD9 signaling activatesCandida albicans–specific Th-17 T cell responsesupon fungal infection in vivo.15

CARD9 can also be triggered by adju-vant in vivo. Combination of ovalbumin asa model antigen together with the specificDectin-1 ligand Curdlan induces combinedantigen-specific Th-1 and Th-17 immune

responses and in addition ovalbumin-specificimmunoglobulin. TLR ligands as control adju-vants were insufficient for the induction of Th-17 responses.15 The Dectin-1/CARD9 path-way is thus a bona fide pattern-recognitionpathway that can couple innate to adaptive im-munity and bias T cell responses toward theTh-17 lineage.

Conclusions

Recent work established CARD9 as a cen-tral integrator of innate immune cell acti-vation. Various upstream receptors that en-gage CARD9 signaling were recognized, andCARD9 downstream effector pathways havebeen identified. It is becoming clear thatCARD9 orchestrates responses to several vi-ral, bacterial, and fungal pathogens, althoughthe precise contribution of CARD9 signalingto the control of specific infectious diseases isonly beginning to be defined.

How deregulation of CARD9 signalingmight contribute to human immune cell–mediated diseases is also still unclear. Yet, itis conceivable that loss-of-function mutation inthe CARD9 gene could cause susceptibility toinfections, for example in rare cases of familialfungal susceptibility syndromes. On the otherhand, aberrant activation of CARD9, eitherthrough genetic mutations or via environmen-tal factors, could result in pathological immune-cell activation, causing inflammatory diseasesor certain cancers. In this context it is importantto note that an association of a single CARD9nucleotide polymorphism with inflammatorybowel disease has been detected in a Dutchcohort of Crohn disease and ulcerative colitispatients.30 In addition, ectopic overepression ofCARD9 was found in gastric B cell lymphomaspecimens, suggesting that aberrant CARD9expression in B cells could contribute to thesurvival or proliferation of tumor cells poten-tially via NF-κB activation.31,32 More researchis clearly required to define the precise molec-ular mechanism of CARD9 signaling and the


role of this protein and pathway in disease. Re-sults from these efforts will provide new targetsfor the manipulation of immune responses, ei-ther for immune suppression in inflammationor for immune cell activation, for example withCARD9 engaging adjuvant for vaccination.

Acknowledgments

I thank members of the laboratory for helpfuldiscussions. Our work is supported by a Max-Eder-Program grant from Deutsche Krebshilfeand by SFB grants from Deutsche Forschungs-gemeinschaft.

Conflicts of Interest

The author declares no conflicts of interest.

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CARD9 Signaling in the Innate Immune Response