The Inflammasomes in Autoinflammatory Diseases ...

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The Inflammasomes in Autoinflammatory Diseases with Skin Involvement Hans-Dietmar Beer1,2, Emmanuel Contassot1,2 and Lars E. French1 During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1b. Consequently, targeting of IL-1b has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling. Journal of Investigative Dermatology advance online publication, 6 March 2014; doi:10.1038/jid.2014.76

INTRODUCTION Our skin, and particularly its outermost part, the epidermis, is regularly exposed to numerous physical, chemical, and biological insults. Integrity and homeostasis are maintained thanks to appropriate defense mechanisms that include the epidermal barrier and adequate innate immune responses. The latter can be triggered by a large variety of insults in a very rapid but relatively unspecific manner through the recognition of conserved exogenous and endogenous molecules that are sensed by a number of mechanisms, including multimolecular intracellular protein complexes called inflammasomes. The first report of an inflammasome as a molecular platform triggering inflammation was made in August 2002 (Martinon et al., 2002). Since then, a large body of basic and translational research has shown that the inflammasome is an important component of the innate immune response critically involved in inflammation.

INFLAMMASOMES Toll-like receptors are able to induce an inflammatory response. They do so through the induction of inflammatory gene expression upon sensing of pathogen-associated molecular patterns that are conserved molecules from microbes (Beutler, 2009). In contrast, inflammasomes mount an inflammatory response by different mechanisms and pathways (see below) (Strowig et al., 2012). Interestingly, they assemble not only upon sensing of pathogen-associated molecular patterns but also when cells, usually macrophages or dendritic cells, come into contact with endogenous molecules released by damaged or injured cells, thus termed danger- or damage-associated molecular patterns (DAMPs). Activation of Toll-like receptors is in part a prerequisite for inflammasome activation or for their downstream pathways, as this priming induces expression of certain inflammasome proteins (e.g., NLRP3 (NOD,

leucine-rich repeat and pyrin domain containing protein 3)) or of their downstream target proIL-1b (Burns et al., 2003; Bauernfeind et al., 2009). All inflammasomes consist of a central scaffold and sensor protein (a Nod-like receptor: NLRP1, NLRP3, NLRC4, and NLRP6 or an HIN (hematopoietic IFNinducible nuclear antigen) domain protein: AIM2 (absent in melanoma 2) or IFI16 (IFN-g-inducible protein 16)), the adaptor protein ASC (apoptosisassociated speck-like protein containing a CARD), and the effector protein caspase-1. In addition to this core composition, other proteins including NAIPs (NLR family, apoptosis inhibitory proteins), PKR (double-stranded RNAdependent protein kinase), or caspase-4 have been identified that are necessary for the activation of one or several types of inflammasomes (Kofoed and Vance, 2011; Lu et al., 2012; Sollberger et al., 2012). It seems that in most cases, individual pathogen-associated molecular

1

Department of Dermatology, Zu¨rich University Hospital, Zu¨rich, Switzerland

2

These authors contributed equally to this work.

Correspondence: Lars E. French, Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, CH-8091 Zu¨rich, Switzerland. E-mail: [email protected] Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); CAPS, cryopyrinassociated periodic syndrome; DAMP, danger- or damage-associated molecular pattern; HIN, hematopoietic IFN-inducible nuclear antigen; HMGB1, highmobility group box 1; IFI16, IFNg–inducible protein 16; NAIP, NLR family, apoptosis inhibitory protein; NLRC4, NLR family CARD domain containing 4; NLRP, NOD, leucine-rich repeat and pyrin domain containing protein; NOD, nucleotide-binding oligomerization domain; PAPA syndrome, pyogenic arthritis–pyoderma gangrenosum–acne syndrome; PKR, double-stranded RNA-dependent protein kinase; PSTPIP1, proline–serine–threonine phosphatase-interactive protein 1; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; Th17, T helper type 17 Received 4 July 2013; revised 1 October 2013; accepted 2 October 2013

& 2014 The Society for Investigative Dermatology

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H-D Beer et al. Inflammasomes in Autoinflammatory Diseases

patterns and DAMPs activate specific inflammasomes and that pathogens and stress factors, which cause inflammation due to more than a single type of inflammasome, represent exceptions (Wu et al., 2010). AIM2 and IFI16 assemble with ASC and caspase-1 upon direct binding of double-stranded cytoplasmic or nuclear DNA, respectively (Strowig et al., 2012). However, the molecular mechanisms resulting in activation of the other types of inflammasomes are less clear. INFLAMMASOME EFFECTOR MECHANISMS Upon inflammasome assembly, the protease caspase-1 is activated and the cleavage of its known (and unknown) substrates differentially contributes to inflammation. Clearly, biologically inactive proIL-1b is its most important substrate (Dinarello, 2009). This is reflected by the former name of caspase-1, IL-1bconverting enzyme. Mature and active IL-1b is a powerful proinflammatory cytokine critically involved in the induction of an inflammatory response (Dinarello, 2009). Caspase-1 also activates proIL-18, a cytokine involved in the recruitment of T cells and in the induction of IFNg. In contrast to proIL1b, proIL-1a, which binds to the same receptor as IL-1b, is already active. Limited proteolysis enhances the activity of proIL-1a; however, this occurs independently of caspase-1 (Afonina et al., 2011). Still, caspase-1 activity is linked to proIL-1a as the protease can regulate the release of the cytokine and of several other proteins involved in inflammation and repair. ProIL-1a, -b, -18, and additional proteins with an extracellular function lack a signal peptide. Nevertheless, these proteins leave the cell, but they do it independently of the classical secretion pathway by a poorly understood alternative mechanism called unconventional protein secretion that is regulated by caspase-1 activity (Nickel and Rabouille, 2009). However, proIL-1a secretion can also occur independently of caspase-1 (Gross et al., 2012; Lukens et al., 2013) or the cytokine can be active on the cell surface (Fettelschoss et al., 2011). In contrast to most other caspases, caspase-1 is considered to be 2

Journal of Investigative Dermatology

not involved in apoptosis but in a lytic and inflammation-supporting form of programmed cell death named pyroptosis (Bergsbaken et al., 2009). The intracellular bacterium Salmonella typhimurium induces this type of cell death in a NLRC4-dependent but ASCindependent manner in macrophages, but not in neutrophils (Miao and Warren, 2010). Other activators of and cell types for pyroptosis are being discussed (Bergsbaken et al., 2009). Pyroptosis is characterized by DNA fragmentation that occurs without activation of apoptotic caspases and is only dependent on caspase-1. Most importantly, pyroptotic cell death is characterized by cell lysis and the release of DAMPs (that can induce inflammasome activation in other cells) and of additional proinflammatory molecules termed alarmins, such as HMGB1 (high-mobility group box 1) and members of the S100 family, with the latter activating Toll-like receptors. The existence of these IL-1bindependent effector mechanisms of inflammasomes raise the possibility that diseases with an involvement of inflammasomes are not always primarily mediated by IL-1b and can consequently not be efficiently treated by IL-1 blockers. INFLAMMASOME ACTIVITY IN KERATINOCYTES In addition to their mechanical barrier function, keratinocytes are immunologically active, responding to injuries and danger signals by secreting proinflammatory cytokines. Although inflammasomes have been mainly characterized in professional immune cells such as macrophages and dendritic cells, at least the NLRP1, NLRP3, and AIM2 inflammasomes are also expressed by keratinocytes. UVB irradiation activates the NLRP1 and NLRP3 inflammasomes with subsequent IL-1b secretion in human primary keratinocytes in a cytoplasmic Ca2 þ concentration–dependent manner (Feldmeyer et al., 2007). In addition, the NLRP3 inflammasome in keratinocytes is able to sense different contact sensitizers and is involved in the sensitization phase of contact hypersensitivity (CHS) (Watanabe et al., 2007). In psoriasis, cytosolic DNA,

which is detected in keratinocytes of lesional skin, is suspected to act as a DAMP activating the AIM2 inflammasome (Dombrowski et al., 2011). The AIM2 inflammasome is also activated by human papillomavirus 16 and honey bee venom (Dombrowski et al., 2012; Reinholz et al., 2013). In spite of the above evidence that keratinocytes can effectively mount innate immune responses to DAMPs, their contribution in the cutaneous manifestations of autoinflammatory diseases has not been investigated to date. AUTOINFLAMMATORY DISEASES Inflammasomes have not only a crucial and beneficial role in many pathogenor danger-induced acute inflammations, but can also cause a relatively new family of so-called autoinflammatory diseases (Dinarello, 2009) (Figure 1). These diseases are characterized by seemingly unprovoked inflammation in the absence of high-titer antibodies and antigen-specific T cell responses (Masters et al., 2009). Interestingly, several of them are characterized by cutaneous neutrophilic inflammation and skin signs are important markers of disease activity. Most importantly, autoinflammatory diseases respond well to the treatment with different IL-1 blockers such as Anakinra, the recombinant version of the naturally occurring IL-1 receptor antagonist. Consequently, autoinflammatory diseases have also been defined by their responsiveness to IL-1 blockade (Dinarello, 2009) (Figure 2 and Table 1). Cryopyrin-associated periodic syndromes

Cryopyrin-associated periodic syndromes (CAPS) are prototypic autoinflammatory diseases caused by autosomal dominant mutations in the NLRP3 gene (Hoffman et al., 2001; Agostini et al., 2004). CAPS include familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CAPS are characterized by periodic fever syndromes associated with urticaria-like skin lesions. In CAPS patients, the mutations identified in NLRP3 markedly lower its activation threshold, thus


IL-1β IL-1RA IL-

IL-1β

A 1R

Normal situation

Mutated NLRP3

ASC

IL-1RI IL-1RAcP DIRA

PYD

Familial Mediterranean fever

PYD

Pyrin

CARD

PSTPIP1

CASP-1 CARD

PAPA syndrome

NACHT

LRRs

CAPS: cryopyrin-associated periodic syndromes

Caspase-1

Pro-IL-1β

Figure 1. Deregulation of IL-1b production and signaling is associated with autoinflammatory disorders. Mutations in the NLRP3 gene lead to a constitutive inflammasome activation in CAPS patients. Hyperphosphorylated variants of PSTPIP1 such as the ones causing PAPA syndrome are known to have a higher affinity for pyrin than wild-type PSTPIP1. The binding of PSTPIP1 variants to the regulatory domain of pyrin relieves its inhibitory activity, resulting in pyrin activation and subsequent ASC oligomerization and caspase-1 activation in PAPA syndrome, thereby relating PAPA syndrome and familial Mediterranean fever. In DIRA, the absence of IL-1RA production leads to an uncontrolled IL-1 overactivity. ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain; CAPS, cryopyrin-associated periodic syndrome; DIRA, deficiency of IL-1 receptor antagonist; IL-1RA, IL-1 receptor antagonist; LRR, leucine-rich repeat; PAPA, pyogenic arthritis–pyoderma gangrenosum–acne; PSTPIP1, proline–serine–threonine phosphatase-interactive protein 1.

Ilaris (Canakinumab)

Kineret (Anakinra)

IL-1β

Xoma 052 Arcalyst (Gevokizumab) (Rilonacept) IL-1β

IL-1β

IL-1RI Figure 2. Current IL-1b-blocking strategies. Clinically available drugs consist of soluble recombinant IL-1RA (Anakinra), blocking anti-IL-1b antibodies (Canakinumab and Gevokizumab), and a dimeric fusion protein consisting of the ligand-binding domains of IL-1R1 and IL-1 receptor accessory protein (IL-1RAcP) linked to the human Fc fragment of IgG1 (Rilonacept). IL-1RA, IL-1 receptor antagonist.

leading to seemingly unprovoked activation of caspase-1 and subsequent abnormal IL-1b secretion (Agostini et al., 2004). Mice expressing human NLRP3 mutants develop clinical manifestations of CAPS and exhibit features recapitulating the human disease with notably overt neutrophilic skin infiltration and a T helper type 17 (Th17) cytokine profile in skin lesions (Brydges et al., 2009). The T cell response in the skin of CAPS patients appears to be limited to IL-1b-dependent Th17, and

does not involve Th1 or Th2, as observed in CHS. Therefore, although IL-1b has a key role in both CHS and CAPS pathogenesis, additional conditions such as the presence of exogenous antigen(s), as is the case for CHS, may account for different manifestations involving subset-dependent CD4 þ T cell–driven pathomechanisms. In accordance with the pathogenetic role of IL-1b in CAPS, IL-1 inhibitors are extremely successful for their treatment (Hoffman et al., 2004, 2008;

Lachmann et al., 2009; Kone-Paut et al., 2011). Studies in mice expressing Nlrp3 mutants mimicking the mutations found in human CAPS (Brydges et al., 2009; Meng et al., 2009) suggest that skinresident immune cells may be responsible for the abnormal IL-1b production. Indeed, the two initial reports describing the development of neutrophil-rich dermatitis resembling human CAPS showed that the priming of macrophages from Nlrp3-mutant mice with Toll-like receptor agonists alone (signal 1) induced a robust IL-1b production and that Nlrp3 mutations in bone marrow–derived cells are sufficient to induce a CAPS phenotype in mice (Meng et al., 2009). Consistently, with these observations in mice, it has been observed that most of the IL-1bpositive cells in the skin lesions of CAPS patients are mast cells that can produce IL-1b in an Nlrp3-dependent manner (Nakamura et al., 2009). More recently, it has been shown that mast cells have a critical role in triggering the neonatal form of the disease in mice (Nakamura et al., 2012). To date, there are no functional data showing that keratinocytes are directly involved in IL-1b overproduction in autoinflammatory disorders. Because of the propensity of keratinocytes to strongly react to DAMPs, a substantial contribution of keratinocytes to the recruitment of neutrophils to the skin via IL-1b cannot be excluded. Schnitzler’s syndrome

Schnitzler’s syndrome is characterized by chronic urticaria and an IgM gammopathy accompanied by recurrent fever, arthritis or arthralgia, and bone pain among others (Asahina et al., 2010). The exact etiology and pathogenesis of Schnitzler’s syndrome remain to be clarified, but IL-1b appears to crucially contribute to the systemic inflammation occurring in these patients as enhanced IL-1 secretion by peripheral blood mononuclear cells from patients can be normalized by Anakinra (Launay et al., 2013), and Anakinra (Volz et al., 2012), Rilonacept (Krause et al., 2012) and Canakinumab have emerged as effective therapeutic options (de Koning et al., 2011). www.jidonline.org

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Table 1. Autoinflammatory disorders with skin involvement Disease

Defective molecule

Inheritance

IL-1-targeting treatment

Target molecule

FCAS

NLRP3

Autosomal dominant

Anakinra Rilonacept Canakinumab

IL-1R1 IL-1b IL-1b

MWS

NLRP3

Autosomal dominant


IL-1R1 IL-1b IL-1b

CINCA

NLRP3

Autosomal dominant

Anakinra Canakinumab

IL-1R1 IL-1b

CAPS

Other inflammatory disorders DIRA

IL-1RA

Autosomal recessive

Anakinra

IL-1R1

PAPA syndrome

PSTPIP1

Autosomal dominant

Anakinra

IL-1R1

Schnitzler’s syndrome

Unknown

Unknown


IL-1R1 IL-1b IL-1b

SAPHO

Unknown

Unknown

Anakinra

IL-1R1

Abbreviations: CAPS, cryopyrin-associated periodic syndrome; CINCA, chronic infantile neurological cutaneous and articular syndrome; DIRA, deficiency of IL-1 receptor antagonist; FCAS, familial cold autoinflammatory syndrome; IL-1RA, IL-1 receptor antagonist; MWS, Muckle–Wells syndrome; NLRP3, NOD, leucine-rich repeat and pyrin domain containing protein 3; PAPA syndrome, pyogenic arthritis–pyoderma gangrenosum–acne syndrome; PSTPIP1, proline– serine–threonine phosphatase-interactive protein 1; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.

Deficiency of IL-1 receptor antagonist (DIRA)

DIRA is a severe autosomal recessive inherited disease caused by the homozygous loss-of-function mutations in IL1RN leading to the absence of IL-1 receptor antagonist production and subsequent IL-1 overactivity (Aksentijevich et al., 2009; Reddy et al., 2009). Clinically, DIRA manifests itself with perinatal-onset pustular dermatitis, joint swelling, painful osteolytic lesions, and periosteitis. Treatment with Anakinra, a soluble recombinant IL-1 receptor antagonist, induces rapid and complete clinical improvement (Aksentijevich et al., 2009; Schnellbacher et al., 2012). PAPA syndrome

PAPA (pyogenic arthritis–pyoderma gangrenosum–acne) syndrome is an inherited disorder caused by an autosomal dominant mutation in PSTPIP1 (proline–serine–threonine phosphataseinteractive protein 1) (Nesterovitch et al., 2011). A deregulation of caspase-1 activation and an increased production of IL-1b as well as tumor necrosis factor in peripheral blood mononuclear cells have been reported (Shoham et al., 2003; Cortis et al., 4


2004). PSTPIP1 mutants have been shown to induce proIL-1b processing by caspase-1 (Yu et al., 2007; Wang et al., 2013) and Anakinra has been shown to be effective in the control of inflammatory manifestations in certain patients (Dierselhuis et al., 2005; Brenner et al., 2009). SAPHO syndrome

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is characterized by the association of cutaneous manifestations—in particular, pustular psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, and severe acne—with inflammatory osteoarthropathy. Anakinra has proven to be efficient in the treatment of SAPHO (Wendling et al., 2012), suggesting that IL-1 may have an important but not unique role in treatment, as anti-tumor necrosis factor agents have also been reported to induce a positive response in SAPHO patients (Wagner et al., 2002). CONCLUSION The discovery of the inflammasomes a decade ago and the new understanding of regulation mechanisms of IL-1b have shed light on the critical role of this

cytokine in the etiopathogenesis of the spectrum of clinical disorders now known as autoinflammatory diseases, which are considered to be distinct from autoimmune and allergic diseases. Interestingly, a common denominator in these diseases is the neutrophil-rich nature of the inflammation with a skin involvement. However, the nature of the cells abnormally producing IL-1b in the skin of patients with autoinflammatory disorders remains to be determined. Indeed, to our knowledge, functional studies in these patients have been performed using peripheral blood cells. Therefore, the respective contribution of skin cell types such as keratinocytes or macrophages to the cutaneous manifestations of autoinflammation remains to be investigated. Murine models based on conditional, cell type–specific knockin of inflammasome mutants would be of great interest to address this issue. In addition, we are far from understanding individual, patient-specific factors or from obtaining the answer to the question of why the skin tolerates certain bacteria and substances, whereas others cause an inflammation. Of further interest to clinicians in search for the etiology of disease is the fact that acne,


pyoderma gangrenosum, psoriasiform pustulosis, and urticaria-like lesions are also clinical presentations observed in autoinflammatory diseases resulting from a deregulation of IL-1. This raises the question as to a possible role of the inflammasomes and/or IL-1 in more common neutrophilic dermatoses such as acne, pyoderma gangrenosum, hidradenitis suppurutiva, pustular psoriasis, Sweet’s syndrome, and acute generalized exanthematic pustulosis. Although the etiology and physiopathology of some autoinflammatory disorders remain enigmatic, targeted therapies against IL-1 have proven to be efficient and induce sustained remission in a substantial number of patients. Further investigation of the molecular nature of the above diseases may prove that IL-1, downstream cytokines induced by IL-1 signaling, T cell subtypes such as Th17 that are partially dependent on IL-1b for their phenotypic maturation, or other inflammasome effector mechanisms have a role in their pathogenesis. The increasing number of agents for targeting these pathways that are currently available or under development in clinical trials promises a better future for clinicians taking care of patients with such diseases.

CONFLICT OF INTEREST The authors state no conflict of interest.

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