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. 2020 Jul;12(7):a037036. doi: 10.1101/cshperspect.a037036

Dysregulation of Cell Death in Human Chronic Inflammation

Yue Li 1, Christoph Klein 1, Daniel Kotlarz 1
PMCID: PMC7328459  PMID: 31843991

Abstract

Inflammation is a fundamental biological process mediating host defense and wound healing during infections and tissue injury. Perpetuated and excessive inflammation may cause autoinflammation, autoimmunity, degenerative disorders, allergies, and malignancies. Multimodal signaling by tumor necrosis factor receptor 1 (TNFR1) plays a crucial role in determining the transition between inflammation, cell survival, and programmed cell death. Targeting TNF signaling has been proven as an effective therapeutic in several immune-related disorders. Mouse studies have provided critical mechanistic insights into TNFR1 signaling and its potential role in a broad spectrum of diseases. The characterization of patients with monogenic primary immunodeficiencies (PIDs) has highlighted the importance of TNFR1 signaling in human disease. In particular, patients with PIDs have revealed paradoxical connections between immunodeficiency, chronic inflammation, and dysregulated cell death. Importantly, studies on PIDs may help to predict beneficial effects and side-effects of therapeutic targeting of TNFR1 signaling.

Inflammation is a protective mechanism in host defense and wound healing during tissue damage or infection (Medzhitov 2008). The degree of inflammation depends on the infectious or toxic triggers and on host susceptibility. Inflammatory responses are complex processes involving vascular permeability, inflammatory mediators (e.g., chemokines, adhesion molecules, cytokines, enzymes), detecting sensors, and extracellular matrix components, as well as recruitment of circulating inflammatory cells, activation of resident immune cells, and adaptive immunity.

Inflammatory mediators, danger-associated molecular patterns (DAMPs), and hypoxia lead to recruitment and degranulation of platelets and resident mast cells as well as activation of tissue-resident immune cells. The release of chemoattractants orchestrates leucocyte migration to the site of inflammation (Medzhitov 2008). Neutrophils with phagocytotic and microbicidal functions are recruited from the circulation as well. Initially, neutrophils potentiate the proinflammatory environment to eliminate inflammatory agents, but apoptosis and clearance of neutrophils are central processes in the resolution of inflammation (Mantovani et al. 2011). Circulating monocytes enter the site of inflammation and differentiate into tissue macrophages that phagocytose foreign particles, debris, and apoptotic cells. The clearance of apoptotic neutrophils triggers a switch from a pro- to an anti-inflammatory program in macrophages. In the late phase of inflammation, lymphocytes will be recruited and mediate adaptive immunity (Serhan and Savill 2005). Coordinated networks are required to resolve and control inflammatory processes. Excessive and uncontrolled inflammation caused by failure to remove noxious materials and apoptotic inflammatory cells may contribute to autoinflammation, autoimmunity, degenerative diseases, allergy, and malignancies (Silva et al. 2008).

Inflammation and cell death are intertwined biological processes sharing many receptors and effector molecules. The release of proinflammatory factors by dying cells may facilitate recovery or extension of inflammation, but accumulating evidence suggests that perturbed cell-death responses may actively contribute to inflammation (Rock and Kono 2008). Whereas necroptosis and pyroptosis release DAMPs (for example, ATP, DNA, and uric acid) through permeabilized membranes and are primarily considered to enhance inflammation, apoptosis contains cytoplasmic content and is thought to be critical in the termination process (Rock and Kono 2008). While different forms of cell death share morphological and biochemical similarities, the molecular characteristics and host responses can be drastically different depending on the biological context. The fate decision of cell death versus inflammation is tightly controlled by multiple pathways, including proinflammatory tumor necrosis factor receptor 1 (TNFR1) signaling. Mouse studies have unveiled mechanistic insights on the regulation of TNFR1 signaling and how it may contribute to disease (Fig. 1; Silke et al. 2015). The characterization of patients with monogenic primary immunodeficiencies (PIDs) has shown the critical role of TNFR1 signaling in human disease and highlighted paradoxical links between immunodeficiency and dysregulation of cell death in chronic inflammation (Table 1). Here, we review recent insights with a focus on novel inherited errors of human immunity.

Figure 1.

Figure 1.

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The tumor necrosis factor receptor 1 (TNFR1) signaling pathway as a master regulator of inflammation and cell death. TNFR1 encountering TNF nucleates complex I, which includes TNFR1-associated death domain protein (TRADD), receptor-interacting protein kinase 1 (RIPK1), TNFR1-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), and the linear ubiquitin chain assembly complex (LUBAC) composed of heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), HOIL1-interacting protein (HOIP), and SHANK-associated RH domain-interacting protein (SHARPIN). Polyubiquitinated RIPK1 recruits the IκB kinase (IKK) complex (composed of the NF-κB essential modulator [NEMO], IKKα, and IKKβ) and the TAK1 complex, which mediate NF-κB and MAPK signaling. Degradation of phosphorylated IκB mediates translocation of p50 and RelA to the nucleus and transcription of proinflammatory and prosurvival NF-κB target genes. The stability of complex I is regulated by deubiquitinating enzymes such as A20, cylindromatosis (CYLD), and OTU deubiquitinase with linear linkage specificity (OTULIN). Formation of complex II containing Fas-associated protein with death domain (FADD), caspase-8, TRADD, and RIPK1 can trigger apoptosis. If the activity of caspase-8 is compromised, RIPK3 interacts with RIPK1 via its RHIM domain. Autophosphorylated RIPK3 leads to recruitment, phosphorylation, and oligomerization of the pseudokinase mixed lineage kinase domain-like (MLKL). Translocation of activated MLKL to the plasma membrane results in necroptosis. Proteins highlighted by red frames indicate that mutations in the corresponding genes have been reported as monogenic causes for primary immunodeficiencies.

Table 1.

Phenotypes of constitutive knockout mouse models and patients with monogenic immune-related disorders affecting tumor necrosis factor receptor 1 (TNFR1) signaling

Genes (mouse/human) Mouse Human
Casp8/CASP8 Embryonic lethality; cardiac deformations; neural tube defects; hematopoietic progenitor dysfunctions (Varfolomeev et al. 1998) ALPS-like disorder (lymphadenopathy, splenomegaly, immunodeficiency with defective activation of T, B, and NK cells (Chun et al. 2002) Late-onset multiorgan lymphocytic infiltrations with granulomas (Niemela et al. 2015) Immunodeficiency (increased susceptibility to viral and bacterial infections, defects in T and B cells) and VEO-IBD (Lehle et al. 2019)
Chuk/CHUK (IKKα) Perinatal lethality; impaired limb outgrowth; skeletal morphogenesis; epidermal defects (Hu et al. 1999; Takeda et al. 1999) Abortions; multiple fetal malformations (e.g., craniofacial abnormalities and absent limbs) (Lahtela et al. 2010)
Cyld/CYLD Autoimmunity; abnormal thymocyte development; impaired lymphocyte activation; B-cell hyperplasia (Reiley et al. 2006; Zhang et al. 2006) Phenotypic heterogeneity including cylindromatosis, multiple familial trichepithelioma type I, and Brooke–Spiegler syndrome (Bignell et al. 2000; Mathis et al. 2015)
Fadd/FADD Embryonic lethality as a result of defective vascular development (Yeh et al. 1998) Immunodeficiency (bacterial and viral susceptibility); functional hyposplenism; febrile episodes; encephalopathy; developmental abnormalities (Bolze et al. 2010)
Ikbkb/IKBKB (IKKβ) Embryonic lethality; TNFR1-dependent hepatocyte apoptosis and degeneration (Li et al. 1999; Tanaka et al. 1999) Severe combined immunodeficiency (hypogammaglobulinemia or agammaglobulinemia, peripheral T and B cells are exclusively of naive phenotype, absence of regulatory T cells and γδ T cells, impaired lymphocyte activation) (Pannicke et al. 2013)
Ikbkg/IKBKG (NEMO) Males: embryonic lethality; liver degeneration; defective generation and/or persistence of lymphocytes Females: severe skin lesions with extensive granulocyte infiltration and hyperproliferation; hepatocyte and keratinocyte apoptosis (Schmidt-Supprian et al. 2000) Loss-of-function mutations: incontinentia pigmenti (Smahi et al. 2000) Hypomorphic mutations: X-linked ectodermal dysplasia with immunodeficiency and diverse clinical manifestations (e.g., life-threatening infections, inflammatory diseases, osteopetrosis, lymphedema) (Zonana et al. 2000; Döffinger et al. 2001)
Mlkl/MLKL No detectable abnormality in the development of immune cells (Wu et al. 2013) No human disease identified
Nfkb1/NFKB1 Intestinal inflammation; B-cell dysfunction; defective adaptive immunity in response to infections (Sha et al. 1995) Haploinsufficiency: common variable immunodeficiency with recurrent respiratory infections; hypogammaglobulinemia; autoimmunity; progressing pulmonary disease (Chen et al. 2013; Fliegauf et al. 2015) Loss of function: lymphadenopathy; splenomegaly; autoimmunity; defects in B-cell differentiation (Tuijnenburg et al. 2018)
Nfkbia/NFKBIA (IκBα) Early neonatal lethality; severe inflammatory dermatitis; enhanced granulopoiesis (Beg and Baltimore 1996; Klement et al. 1996) Knockin mice (Ser32Ile): immunodeficiency; defective lymphoid organogenesis (Mooster et al. 2015) Gain-of-function mutations: EDA-ID; T- and B-cell deficiencies with increased susceptibility to infections (Courtois et al. 2003; Boisson et al. 2017)
Otulin/OTULIN Embryonic lethality; compromised craniofacial and neuronal development; impaired angiogenesis (Rivkin et al. 2013) Fatal autoinflammation; recurrent nodular panniculitis; lipodystrophy; diarrhea; joint swelling; failure to thrive (Damgaard et al. 2016; Zhou et al. 2016b)
Rbck1/RBCK1 (HOIL) Embryonic lethality; disrupted vascular architecture and cell death in the yolk sac endothelium (Peltzer et al. 2018) Immunodeficiency (susceptibility to pyogenic bacterial infections) and autoinflammation (hyperresponsiveness to IL-1β); amylopectinosis (Boisson et al. 2012)
Rela/RELA Embryonic lethality; TNF-mediated cell death of hepatocytes, macrophages, and fibroblasts (Beg and Baltimore 1996) Chronic mucocutaneous ulceration; increased apoptosis of fibroblasts in response to TNF; impaired NF-κB activation in fibroblasts and PBMCs; impaired stromal cell survival (Badran et al. 2017)
Ripk1/RIPK1 Perinatal lethality; massive apoptosis in lymphoid and adipose tissue; multiorgan hyperinflammation (Kelliher et al. 1998) Life-threatening immunodeficiency (lymphopenia, recurrent infections, defective differentiation of T and B cells); VEO-IBD; arthritis (Cuchet-Lourenço et al. 2018; Li et al. 2019)
Ripk3/RIPK3 Viable and fertile (Newton et al. 2004) No human disease identified
Rnf31/RNF31 (HOIP) Embryonic lethality; defective vascularization caused by aberrant endothelial cell death (Peltzer et al. 2014) Multiorgan autoinflammation (hyperreactive monocytes in response to IL-1β); combined immunodeficiency (recurrent viral and bacterial infections, lymphopenia, antibody deficiency, impaired B-cell activation, and differentiation in response to CD40, impaired T-cell distribution and functions); subclinical amylopectinosis; systemic lymphagiectasia (Boisson et al. 2015)
Sharpin/SHARPIN Liver inflammation; splenomegaly; severe eosinophilic skin inflammation; defective lymphoid organogenesis associated with excessive TNFR1-mediated death (Kumari et al. 2014; Rickard et al. 2014a) No human disease identified
Tnfaip3/TNFAIP3 (A20) Perinatal lethality or lethality shortly after birth; severe multiorgan inflammation (e.g., liver, kidneys, intestines, joints, and bone marrow) (Lee et al. 2000) Early-onset systemic autoinflammatory syndrome resembling Behcet's disease (Zhou et al. 2016a)
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MULTIMODAL TNFR1-DEPENDENT SIGNALING DETERMINES INFLAMMATORY AND CELL-DEATH FATES

TNF plays a critical role in regulating host defense, but can also be pathogenic in several inflammatory conditions (Monaco et al. 2015). TNFR1 signaling intertwines inflammation and cell death by engaging IKK/NF-κB and caspase-8/receptor interacting protein kinase 1 (RIPK1)/RIPK3 signaling (Fig. 1; Kalliolias and Ivashkiv 2016). TNF is produced by several immune, epithelial, endothelial, and stromal cell types (Grivennikov et al. 2005). Upon binding of TNF to trimeric TNFR1, a membrane-associated complex I is formed by recruitment of the adaptor protein TNFR1-associated death domain protein (TRADD), TNFR1-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), RIPK1, and linear ubiquitin chain assembly complex (LUBAC) (Micheau and Tschopp 2003; Kirisako et al. 2006). The latter is composed of heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), HOIL-1-interacting protein (HOIP), and SHANK-associated RH domain-interacting protein (SHARPIN) (Kirisako et al. 2006; Gerlach et al. 2011; Ikeda et al. 2011; Tokunaga et al. 2011). Modification of RIPK1 and possibly other complex I components with Lys63-linked polyubiquitin assembled by cIAP1/2, and Met1-linked ubiquitin assembled by LUBAC, mediates activation of TGF-β-activated kinase 1 (TAK1) and IκB kinase (IKK) (Micheau and Tschopp 2003; Wang et al. 2008). Activated TAK1 and IKK induce MAPK signaling and ubiquitin–protein system-mediated degradation of IκB leading to NF-κB activation.

Compromised prosurvival signaling emanating from complex I results in the formation of alternative cytosolic TNF-induced complexes mediating apoptosis and necroptosis (Van Antwerp et al. 1996). Proinflammatory NF-κB signaling can be terminated by disassembly of complex I through A20- and cylindromatosis (CYLD)-mediated deubiquitylation of RIPK1 and TRAF2 (Wertz et al. 2004; Wang et al. 2008). Formation of cytosolic complexes containing TRADD, Fas-associated protein with death domain (FADD), RIPK1, and procaspase-8 (Micheau and Tschopp 2003; Wang et al. 2008) can lead to homodimerization and activation of caspase-8, with subsequent cleavage of caspase-3 and -7 mediating extrinsic apoptosis (Boatright et al. 2003; Micheau and Tschopp 2003). Apoptosis is the best-defined form of programmed cell death with characteristic morphological and biochemical changes such as nuclear envelope disassembly, cytoplasmic condensation and fragmentation, membrane blebbing, and formation of membrane-bound bodies (Green et al. 2009). Apoptosis plays a pivotal role in controlling immune cell development and homeostasis, by eliminating self-reactive, overactivated, and infected immune cells (Green et al. 2009). Apoptotic cells are ingested by phagocytes before they can release immunogenic intracellular contents, and this prevents activation of the innate immune system (Green et al. 2016). Impaired apoptosis has been implicated in the pathogenesis of immune-related disease conditions, as exemplified by autoimmune lymphoproliferative syndrome (ALPS) (Fisher et al. 1995; Rieux-Laucat et al. 1995; Drappa et al. 1996).

When the activity of caspase-8 is compromised, necroptosis is initiated by heterodimerization of RIPK1 and RIPK3 via their RIP homotypic interaction motif (RHIM) (Cho et al. 2009; He et al. 2009). Oligomerization and autophosphorylation of RIPK3 result in the recruitment and phosphorylation of the pseudokinase MLKL (Murphy et al. 2013). Subsequent oligomerization and translocation of MLKL to the plasma membrane lead to cell rupture (Petrie et al. 2019). The release of DAMPs from necroptotic cells may be highly immunogenic (Oberst et al. 2011). Altered necroptosis has been implicated in malignancies as well as several pathological inflammatory conditions, including infectious, cardiovascular, neurological, renal, and hepatic diseases (Weinlich et al. 2017). Moreover, several mouse studies have shown that deletion of Mlkl can partially ameliorate inflammation (Rickard et al. 2014a,b; Alvarez-Diaz et al. 2016), indicating that necroptosis may contribute to the pathogenesis of inflammatory disorders. In contrast, necroptosis may benefit host defense against viruses such as herpes simplex virus 1 by eliminating infected cells (Huang et al. 2015; Guo et al. 2018).

Multimodal TNFR1 signaling governs the transition between inflammation, survival, and programmed cell death. However, the exact physiological mechanisms triggering the transition from prosurvival to prodeath responses are still unclear. The complexity of TNFR1 signaling will be further modulated by cross talk with other signaling pathways that can engage with inflammatory and cell-death modules. Dysregulation of components involved in TNFR1 signaling can lead to chronic inflammation. Correspondingly, inhibition of TNF is an effective treatment for several autoinflammatory and autoimmune disorders.

INFLAMMATION IN MONOGENIC DISORDERS AFFECTING TNFR1-MEDIATED SIGNALING

Caspase-8 Deficiency

Caspase-8 is an initiator cysteinyl aspartate-specific protease critical for receptor-mediated apoptosis induced by TNF, TRAIL, and Fas ligand (FASL) (Boldin et al. 1996; Muzio et al. 1996; Ashkenazi and Dixit 1998). The zymogen procaspase-8 consists of two amino-terminal death effector domains (DEDs) and a carboxy-terminal protease domain with two catalytic subunits (p10 and p18) (Earnshaw et al. 1999). Procaspase-8 dimerization via the DED promotes proteolytic cleavage that generates active caspase-8 heterotetramers (p102-p182) (Earnshaw et al. 1999). Active caspase-8 then cleaves and activates the executioner caspases-3 and -7 to induce apoptosis (Earnshaw et al. 1999).

The essential role of caspase-8 in death receptor-induced apoptosis was shown using cells from Casp8 knockout (KO) mice (Varfolomeev et al. 1998). These mice exhibited embryonic lethality associated with cardiac deformations, neural tube defects, and hematopoietic progenitor dysfunctions (Varfolomeev et al. 1998; Sakamaki et al. 2002). Conditional KOs of Casp8 have revealed critical roles for caspase-8 in the response to tissue damage or infection. For example, caspase-8-deficient hepatocytes exhibited impaired proliferation after injury to the liver and this prompted chronic inflammation of the liver (Ben Moshe et al. 2007). Loss of Casp8 in the epidermis also caused inflammation with hyperactive responses to activators of interferon regulatory factor (IRF)3 (Kovalenko et al. 2009). Furthermore, mice lacking caspase-8 in IECs developed spontaneous ileitis that was associated with TNF-induced necroptotic cell death (Günther et al. 2011).

When the activity of caspase-8 is hampered, RIPK1 initiates RIPK3/MLKL-dependent necroptosis (Cho et al. 2009; He et al. 2009; Zhang et al. 2009). Interestingly, most disease phenotypes associated with caspase-8 deficiency in mice were attributed to aberrant necroptosis because they were rescued by loss of Ripk3 or Mlkl (Kaiser et al. 2011; Oberst et al. 2011; Alvarez-Diaz et al. 2016). Mouse studies have also implicated caspase-8 in lymphocyte differentiation and function (Salmena et al. 2003; Kang et al. 2004; Beisner et al. 2005). T-cell-specific deletion of Casp8 resulted in profound depletion of peripheral T cells associated with defective activation and/or survival upon engagement of the T-cell receptor (TCR) (Salmena et al. 2003). These defects impaired CD8+ T-cell-mediated antiviral immunity. Proliferation of caspase-8-deficient T cells could be restored by inhibition of RIPK1 or genetic ablation of Ripk3, implying that caspase-8 suppresses necroptosis during T-cell activation (Bell et al. 2008; Ch'en et al. 2011; Kaiser et al. 2011; Oberst et al. 2011). B-cell-specific deletion of caspase-8 did not impact B-cell development but compromised B-cell activation by Toll-like receptor (TLR) agonists (Lemmers et al. 2007).

The relevance of caspase-8 for human immunity was originally recognized by studies involving two siblings with germline homozygous missense mutations in CASP8 (Chun et al. 2002). Similar to ALPS patients with loss-of-function mutations in genes encoding Fas, FASL, and caspase-10, the patients with germline mutation in CASP8 presented with lymphadenopathy and splenomegaly that was associated with defective Fas-mediated apoptosis in T cells (Chun et al. 2002). The homozygous mutation in CASP8 (Arg248Trp) was located in the p18 protease subunit and it reduced protein stability and enzymatic activity. Unlike typical ALPS, the caspase-8-deficient patients also had defects in the activation of their T-, B-, and natural killer cells causing immunodeficiency (Chun et al. 2002). T-cell dysfunction was associated with impaired TCR-induced nuclear translocation of NF-κB (Su et al. 2005), but given the later studies in mice (Bell et al. 2008; Ch'en et al. 2011; Kaiser et al. 2011; Oberst et al. 2011), the question became whether the defects in NF-κB signaling were a consequence of aberrant necroptosis.

The clinical spectrum of caspase-8 deficiency was further broadened by the description of two patients with the mutation Arg248Trp. These patients presented with late-onset multiorgan lymphocytic infiltrations with granulomas (Niemela et al. 2015). By contrast, Lehle et al. recently described patients with homozygous missense mutations in CASP8 (Gln237Arg) that affect the cleavage and activation of caspase-8 (Lehle et al. 2019). These patients had life-threatening very early-onset inflammatory bowel disease (VEO-IBD) and immunodeficiency that was accompanied by increased susceptibility to viral and bacterial infections, marked lymphadenopathy, reduced TCR-dependent T-cell proliferation and activation, and impaired B-cell maturation (Lehle et al. 2019). Mouse studies have previously shown that myeloid cells lacking Casp8 exhibited increased NLRP3-dependent inflammasome activity with enhanced secretion of proinflammatory cytokines IL-1β and IL-18 (Kang et al. 2013). Correspondingly, caspase-8-deficient patient monocytes secreted more proinflammatory IL-1β than control monocytes in response to lipopolysaccharide (LPS) (Lehle et al. 2019). In caspase-8-deficient human BLaER1 monocyte/macrophage models, blockade of either NLPR3-dependent inflammasome activity or MLKL-dependent necroptosis attenuated IL-1β secretion (Gaidt et al. 2016; Lehle et al. 2019). Thus, both pathways are implicated in proinflammatory cytokine responses. These findings are consistent with the notion that necroptosis can activate the NLRP3 inflammasome (Vince and Silke 2016). Targeting necroptosis might present an attractive therapeutic approach in caspase-8-deficient patients with VEO-IBD, but more detailed mechanistic studies are required.

The identification of caspase-8-deficient patients with VEO-IBD underscores the critical function of caspase-8 in maintaining human intestinal epithelial homeostasis (Lehle et al. 2019). Whereas TRAIL triggered cell death in healthy donor-derived intestinal organoids, caspase-8-deficient cells were unresponsive to TRAIL. In contrast to mouse organoids with loss of Casp8 (Günther et al. 2011), patient-derived caspase-8-deficient intestinal organoids did not exhibit a marked increase in TNF-induced cell death (Lehle et al. 2019). Further studies are needed to determine genotype–phenotype correlations of the mutations in human CASP8. The physiological triggers of intestinal inflammation in human caspase-8 deficiency need to be further defined to identify targeted therapies.

FADD Deficiency

FADD is an adaptor protein that recruits caspase-8 to death receptors (Wilson et al. 2009). Mice lacking Fadd show RIPK3- and MLKL-dependent embryonic lethality similar to mice lacking caspase-8 (Yeh et al. 1998; Alvarez-Diaz et al. 2016). T-cell-specific loss of Fadd, similar to caspase-8 deficiency, caused defective T-cell proliferation that was rescued by inhibition of RIPK1 (Osborn et al. 2010). In addition, Osborn et al. observed enlarged lymph nodes and spleen with increased B cells and red blood cells, respectively. Mice lacking Fadd in epidermal keratinocytes or intestinal epithelial cells (IECs) developed severe inflammation (Bonnet et al. 2011; Welz et al. 2011), indicating that FADD is essential for homeostasis in the skin and intestine. Skin inflammation was triggered by RIPK3-dependent necroptosis, and was partially dependent on the catalytic activity of the deubiquitinating enzyme CYLD and/or TNFR1 signaling (Bonnet et al. 2011). Loss of Fadd in IECs caused spontaneous RIPK3-dependent colitis with epithelial erosions and crypt abscesses (Welz et al. 2011). Disease was prevented by deletion of Cyld or Myd88, or by elimination of the microbiota. Thus, TLR signaling activated by bacteria was a key driver of colitis (Welz et al. 2011).

In humans, a homozygous loss-of-function mutation in the death domain of FADD (Cys105Trp) was reported to impair Fas-induced apoptosis, as in patients with ALPS (Bolze et al. 2010). However, the related patients presented with immunodeficiency, bacterial susceptibility, and developmental abnormalities rather than autoimmunity (Bolze et al. 2010). In contrast to KO mouse models, FADD-deficient patients showed normal T-cell proliferation, but impaired interferon-dependent antiviral immunity, leading to increased susceptibility to viral diseases (e.g., varicella zoster, parainfluenza virus, and Epstein–Barr virus).

RIPK1 Deficiency

RIPK1 is a key molecule controlling both inflammation and cell-death responses via scaffolding-dependent and kinase-specific functions (Ofengeim and Yuan 2013). In particular, RIPK1 mediates multimodal TNFR1 signaling depending on the cell type and biological context. While TNF-induced NF-κB nuclear translocation promotes cell survival and inflammation, modulation of signaling cascades can induce caspase-8-mediated apoptosis or RIPK3-dependent necroptosis, as reviewed in Pasparakis and Vandenabeele (2015). RIPK1-deficient mice exhibited perinatal lethality because of multiorgan hyperinflammation that is driven by aberrant caspase-8-dependent apoptosis and MLKL-dependent necroptosis (Kelliher et al. 1998; Dillon et al. 2014; Kaiser et al. 2014; Rickard et al. 2014b). Conditional KO mice have demonstrated the essential role of RIPK1 in controlling immune and intestinal homeostasis. Mice with loss of Ripk1 in IECs developed severe inflammation in the gut because of FADD/caspase-8-dependent apoptosis (Dannappel et al. 2014; Takahashi et al. 2014), whereas keratinocyte-specific RIPK1 KOs developed skin inflammation associated with ZBP1/RIPK3/MLKL-dependent necroptosis (Lin et al. 2016). T-cell-specific deletion of Ripk1 in mice caused severe lymphopenia and defective T-cell proliferation (Dowling et al. 2016). RIPK1 also contributes to the maintenance of peripheral B cells (Zhang et al. 2011). RIPK1-deficient fetal liver-derived mouse macrophages exhibited enhanced inflammasome activity upon LPS priming (Lawlor et al. 2015).

In contrast to RIPK1-deficient mice, knockin mice expressing catalytically inactive RIPK1 D138N or K45A showed no signs of tissue pathology and are protected from TNF-induced acute shock (Berger et al. 2014; Newton et al. 2014; Polykratis et al. 2014). Thus, the kinase activity of RIPK1 is dispensable for suppressing cell death. Necrostatin-1, a small molecule inhibitor of the kinase activity of RIPK1, has been shown to protect mice from retinal degeneration (Murakami et al. 2014), retinitis pigmentosa (Sato et al. 2013), ischemic brain injury (Degterev et al. 2005; Northington et al. 2011), neurodegeneration (Zhu et al. 2011), myocardial infarction, cardiac hypoxia (Smith et al. 2007; Oerlemans et al. 2012), and renal ischemia-reperfusion injury (Lau et al. 2013).

Recently, studies on patients with monogenic defects of RIPK1 have provided critical insights into the role of RIPK1 in human disease. The patients presented with early-onset, life-threatening immunodeficiency and intestinal inflammation (Cuchet-Lourenço et al. 2018; Li et al. 2019; Uchiyama et al. 2019). Some patients showed arthritis (Cuchet-Lourenço et al. 2018), but skin inflammation was not observed, which is in contrast to RIPK1-deficient mice. Human RIPK1 deficiency was associated with impaired T- and B-cell maturation, defective TNF-mediated activation of the NF-κB pathway, and dysregulated cytokine signaling in immune cells. Cuchet-Lourenço et al. (2018) suggested that inflammation in RIPK1-deficient patients was caused by altered cytokine secretion and necroptosis of immune cells. In parallel and independent experiments, Li et al. studied six pedigrees and demonstrated that RIPK1-deficient macrophages exhibited increased inflammasome activity in response to LPS. Inhibition of MLKL- and NLRP3-dependent pathways by small molecule inhibitors attenuated secretion of proinflammatory IL-1β (Li et al. 2019), but the underlying mechanisms are not completely understood. Blockade of IL-1 has not yet been tested in RIPK1-deficient patients.

Since histological examination of gastrointestinal biopsies revealed only occasional apoptotic morphology, Cuchet-Lourenço et al. proposed that dysfunction of the immune system was critical for disease development. The authors concluded that allogeneic hematopoietic stem cell transplantation (HSCT) may constitute a curative therapy and showed resolution of clinical symptoms in one patient (Cuchet-Lourenço et al. 2018). Li et al. (2019) studied RIPK1-deficient IECs as well as hematopoietic cells. RIPK1-deficient IECs were resistant to killing by TNF, suggesting that RIPK1 also plays a critical intrinsic role in controlling epithelial homeostasis. Differences in the observed phenotypes might be because of the treatment of patients with anti-inflammatory drugs and antibiotics, their genetic background, or environmental factors. HSCT might cure cytokine production defects in immune cells, but not intrinsic epithelial defects, similar to NEMO-deficient patients (Miot et al. 2017). The in vivo triggers perturbing epithelial integrity in mice or humans lacking RIPK1 have not been defined. Moreover, the currently reported RIPK1-deficient patients provided no insights into the role of the kinase domain of RIPK1, because the patient-specific mutations reduced expression of RIPK1 protein. Further studies are needed to define genotype–phenotype correlations, triggers, and molecular consequences of human RIPK1 deficiency.

MONOGENIC DEFECTS OF THE NF-κB SIGNALING PATHWAY

NF-κB is a master transcriptional regulator of cell survival and proliferation, innate and adaptive immunity, and inflammation. Consequently, NF-κB signaling must be tightly regulated for tissue and immune homeostasis (Hayden and Ghosh 2011). Abnormal NF-κB signaling might cause defective immune activation, immunodeficiency, autoimmunity, or lymphoid malignancies (Courtois and Gilmore 2006). Human monogenic defects in NF-κB signaling components have been shown to cause severe immune disorders (Hayden and Ghosh 2008) that may vary from phenotypes in mouse models.

The IKK complex is composed of catalytic subunits (IKK1/IKKα, IKK2/IKKβ) and a regulatory subunit (NF-κB essential modulator [NEMO]) (Chen et al. 1996; DiDonato et al. 1997; Yamaoka et al. 1998). Mice lacking IKKβ were embryonic lethal (Li et al. 1999; Tanaka et al. 1999), whereas impaired degradation of IκBα and delayed NF-κB signaling in IKKβ-deficient patients caused severe combined immunodeficiency (Pannicke et al. 2013). Mice lacking IKKα died at birth because of multiple severe malformations and skin defects (Hu et al. 1999; Takeda et al. 1999). Patients with IKKα deficiency manifested with similar phenotypes, but showed more severe craniofacial abnormalities (Lahtela et al. 2010).

Several mouse and human studies have documented that loss of NEMO, the regulatory subunit of the IKK complex, causes defective NF-κB activation. Loss of X-linked Nemo/Ikbkg caused embryonic lethality in male mice, whereas severe skin lesions were observed in heterozygous females (Schmidt-Supprian et al. 2000). Mice with IEC-specific KO of Nemo developed spontaneous colitis with enhanced apoptosis of Paneth cells and impaired expression of antimicrobial factors, which was dependent on the kinase activity of RIPK1 (Vlantis et al. 2016). Mutations in human X-linked NEMO/IKBKG cause varying phenotypes, in particular anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (Zonana et al. 2000; Döffinger et al. 2001) or incontinentia pigmenti (Smahi et al. 2000). Notably, about 25% of patients develop colitis associated with poor HSCT outcome (Hanson et al. 2008; Kawai et al. 2012).

Similar to NEMO deficiency, autosomal-dominant gain-of-function mutations in NFKBIA (encoding IκBα) caused sustained inhibition of NF-κB signaling that leads to EDA-ID, T- and B-cell deficiency, and increased susceptibility to infections (Courtois et al. 2003; Boisson et al. 2017). Knockin mice that are heterozygous for the human NFKBIA mutation (Ser32Ile) developed EDA-ID and lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells. They also failed to develop contact hypersensitivity or form germinal centers, which are features characteristic of defective noncanonical NF-κB signaling through NF-κB2/RelB (Mooster et al. 2015).

Haploinsufficiency of NFKB1 (p105/p50) or NFKB2 (p100/p52) can cause common variable immunodeficiency with recurrent respiratory infections, hypogammaglobulinemia, and autoimmunity (Chen et al. 2013; Fliegauf et al. 2015). In addition, patients with loss-of-function mutations in NFKB1 demonstrated noninfective complications, including lymphadenopathy, splenomegaly, and autoimmunity (Tuijnenburg et al. 2018). It remains to be shown whether the phenotype of pyoderma gangrenosum in patients with monoallelic NFKB1 mutations is caused by dominant-active effects, loss-of-function, or haploinsufficiency. Of note, all patients showed defective B-cell differentiation. Similarly, Nfkb1-deficient mice developed intestinal inflammation that was associated with profound B-cell dysfunction, including defects in proliferation, class-switch recombination, maturation, humoral immunity, cytokine secretion, and susceptibility to infection (Sha et al. 1995; Bendall et al. 1999).

MONOGENIC DISORDERS OF UBIQUITINATION AND DEUBIQUITINATION IN THE TNFR1 SIGNALING CASCADE

The ubiquitin system plays a crucial role in balancing gene activation and cell death (Aksentijevich and Zhou 2017). Perturbed ubiquitination or deubiquitination can result in dysregulation of the immune system (Aksentijevich and Zhou 2017). LUBAC, the E3 ligase composed of HOIL-1, HOIP, and SHARPIN, inhibits TNFR1-mediated cell death by generating linear polyubiquitin chains on NEMO and other complex I components (Peltzer et al. 2014, 2018; Rickard et al. 2014a). Loss of Rnf31 (encoding HOIP) caused embryonic lethality in mice (Peltzer et al. 2014) as a result of aberrant cell death (Peltzer et al. 2018), whereas excessive cell death in Sharpin-deficient mice caused severe eosinophilic skin inflammation and defective lymphoid organogenesis (Kumari et al. 2014; Rickard et al. 2014a). Mice with keratinocyte-specific depletion of LUBAC components developed severe dermatitis caused by FASL-, TRAIL-, and TNF-induced cell death (Taraborrelli et al. 2018).

No human loss-of-function mutations in SHARPIN have been reported yet, but HOIP or HOIL-1 deficiencies cause PID and autoinflammation with overlapping phenotypes such as susceptibility to infections and amylopectinosis (Boisson et al. 2012, 2015). Mutations in RNF31 or RBCK1 (encoding HOIL-1) that impaired the stability of LUBAC attenuated NF-κB signaling in fibroblasts or B cells treated with IL-1β or TNF. However, patient-derived monocytes were hyperresponsive to IL-1β, leading to up-regulation of inflammatory cytokines and chemokines. TNF-inhibitory treatment has been shown to ameliorate pathology temporarily, but autoinflammation was controlled by HSCT in one HOIL-1-deficient patient (Boisson et al. 2012). It is unclear why HOIL-1 and HOIP are essential for embryogenesis in mice, but not humans. Heterogeneity in the genetic background of humans may be a factor, or there may be physiological differences between species.

The deubiquitinases A20, OTULIN, and CYLD are negative regulators of NF-κB signaling (Lork et al. 2017). However, emerging data have also suggested unexpected roles of these deubiquitinases in regulating cell death independent of NF-κB signaling (Draber et al. 2015; Heger et al. 2018; Polykratis et al. 2019). Defects in these genes lead to increased proinflammatory cytokine profiles (Lork et al. 2017). A20 can cleave Lys63-linked polyubiquitin chains on target proteins, such as RIPK1 and NEMO, to inhibit NF-κB signaling, but it is the binding of A20 to Met1-linked ubiquitin chains that appears to limit the formation of complexes that trigger proinflammatory cell death. For example, mice lacking A20 in myeloid cells developed arthritis that was driven by necroptosis and activation of the NLRP3 inflammasome. Analyses of A20 knockin mice indicated that the ubiquitin-binding ZnF7 domain in A20 is critical for preventing arthritis, whereas the deubiquitinating activity of A20 is dispensable (Draber et al. 2015; Polykratis et al. 2019).

A20-deficient mice die shortly after birth showing severe multiorgan inflammation (Lee et al. 2000). Tissue-specific deletion of Tnfaip3 (encoding A20) in lymphocytes, enterocytes, dendritic cells, keratinocytes, mast cells, hepatocytes, and microglial cells has further demonstrated the crucial role of A20 in maintaining immune homeostasis and inhibiting inflammation (Cox et al. 1992; Tavares et al. 2010; Hammer et al. 2011; Wang et al. 2013; Vereecke et al. 2014; Drennan et al. 2016; Maelfait et al. 2016). Genetic variants of human TNFAIP3 are associated with a broad range of inflammatory and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, type I diabetes, celiac disease, Crohn's disease, coronary artery disease in type 2 diabetes, and systemic sclerosis (Ma and Malynn 2012; Zhou et al. 2016a). Mutations causing TNFAIP3 haploinsufficiency led to early-onset systemic autoinflammatory syndrome, resembling Behcet's disease, because of increased NF-κB-mediated proinflammatory cytokine production (Zhou et al. 2016a). The authors did not specifically study cell-death responses, but patient cells treated with LPS showed enhanced cleavage of caspase-1 and secretion of mature IL-1. These findings are reminiscent of RIPK1 and CASP8 deficiencies, and thus it is tempting to speculate that enhanced inflammasome activation is mediated by aberrant necroptosis.

OTULIN cleaves Met1-linked polyubiquitin chains conjugated by LUBAC (Keusekotten et al. 2013). Recent studies have shown that OTULIN promotes rather than counteracts LUBAC activity. Specifically, OTULIN limits autoubiquitination of LUBAC, which would otherwise lead to RIPK1-dependent cell death (Heger et al. 2018). Consequently, Otulin KO mice were embryonic lethal (Rivkin et al. 2013) similar to mice lacking HOIP or HOIL-1 (Peltzer et al. 2014, 2018). Homozygous missense mutations in human OTULIN caused cell-type-specific alterations in NF-κB signaling, fatal autoinflammation with recurrent nodular panniculitis, lipodystrophy, diarrhea, joint swelling, and failure to thrive (Damgaard et al. 2016; Zhou et al. 2016b). Patient-derived monocytes and fibroblasts exhibited increased sensitivity to TNF-induced cell death (Damgaard et al. 2019). Moreover, treatment with anti-TNF neutralizing antibodies could ameliorate inflammation, whereas HSCT induced sustained remission in OTULIN-deficient patients (Damgaard et al. 2019).

CYLD has been extensively studied for its role in removing Lys63- or Met1-linked polyubiquitin chains from proteins mediating NF-κB signaling. For example, CYLD deubiquitinates proteins in TNFR1 complex I, which limits NF-κB signaling and promotes the assembly of cell-death signaling complexes (Draber et al. 2015). It has been suggested that CYLD regulates innate and adaptive immune responses via its negative regulation of NF-κB signaling components, but dysfunctional cell death might also contribute to immune-related phenotypes. Mice lacking CYLD showed autoimmunity associated with abnormal thymocyte development, lymphocyte activation, and B-cell hyperplasia (Reiley et al. 2006, 2007; Zhang et al. 2006; Jin et al. 2007). CYLD deficiency in humans can lead to distinct phenotypes with cylindromatosis and skin manifestations such as multiple familial trichoepithelioma, type I (Mathis et al. 2015; Farkas et al. 2016). The phenotypic heterogeneity of human CYLD deficiency is likely the result of its diverse roles in controlling other NF-κB-independent pathways such as cell-death responses, cell-cycle progression, and microtubule dynamics (Sun 2010; Zhang et al. 2017a).

TNFR1 SIGNALING AS A THERAPEUTIC TARGET—WHAT DO WE LEARN FROM MONOGENIC DISEASES?

Several mouse and human studies indicate the critical role of TNFR1 signaling in health and disease, as reviewed in Brenner et al. (2015). TNF inhibition has proven effective as treatment for several autoinflammatory and autoimmune conditions (Kalliolias and Ivashkiv 2016). However, many patients with inflammatory disorders are refractory to anti-TNF therapy or develop side-effects (Kalliolias and Ivashkiv 2016). Thus, alternative strategies targeting the TNFR1 pathway are needed to expand the therapeutic armamentarium.

RIPK1/RIPK3/MLKL-dependent necroptosis has been implicated in malignancies and several pathological inflammatory conditions (Weinlich et al. 2017). Small-molecule inhibitors targeting RIPK1 kinase activity present attractive therapeutic potential, because mice expressing catalytically inactive RIPK1 develop normally without inflammatory phenotypes (Berger et al. 2014; Newton et al. 2014; Polykratis et al. 2014). The therapeutic potential of RIPK1 inhibitors has been demonstrated in various mouse disease models (Silke et al. 2015). Based on these studies RIPK1 inhibitor programs have successfully passed clinical phase I trials for the treatment of chronic psoriasis, rheumatoid arthritis, and ulcerative colitis (GSK2982772, DNL747) (Harris et al. 2017; Mullard 2018).

Targeting of RIPK3 is a new idea to treat inflammatory diseases, particularly since mice lacking Ripk3 are viable (Newton et al. 2004). However, knockin mice expressing catalytically inactive RIPK3 D161N exhibited caspase-8-dependent embryonic lethality (Newton et al. 2014), raising concerns about the toxic effects of targeting RIPK3. Indeed, inhibitors of RIPK3 (GSK'840, GSK'843, and GSK'872) trigger RIPK3- and caspase-8-dependent apoptosis reminiscent of that seen in RIPK3 D161N mice (Kaiser et al. 2013; Mandal et al. 2014). Thus, further refinement of RIPK3-based therapies is needed.

Blockade of MLKL has been considered as a means of selectively inhibiting necroptosis. For example, necrosulfonamide (NSA), which is a compound that modifies Cys86 of human MLKL to block its oligomerization, has been suggested as a potential therapeutic for neurodegenerative diseases (Zhang et al. 2017b), but it has not been tested in clinical trials. The MLKL inhibitor compound 1 caused cell toxicity at high concentrations, and thus has not been used in clinical applications (Hildebrand et al. 2014). Recently, a new inhibitor (TC13172) targeting Cys86 of MLKL was demonstrated to block the translocation of MLKL to cell membranes in cell lines (Yan et al. 2017).

Inhibitors of caspase-8 have been proposed for patients with dysregulated cell death and/or inflammation. The pancaspase inhibitor Emricasan has antiapoptotic and anti-inflammatory effects, and has been explored for the treatment of liver disease (Frenette et al. 2019; Garcia-Tsao et al. 2019), renal disease, and diabetes (Kudelova et al. 2015). However, inhibition of caspase-8 might induce necroptosis in some cell types and thereby promote inflammation.

As a master regulator of immunity, NF-κB has been implicated in various autoimmune diseases (Herrington et al. 2016). Selective targeting of NF-κB activity presents another line of therapeutic modulation, but specificity is a major challenge. Commonly used anti-inflammatory agents, such as antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoids have been shown to partly modulate NF-κB signaling at various levels (Yamamoto and Gaynor 2001; Herrington et al. 2016). Specific inhibitors of NF-κB, such as caffeic acid phenethyl ester and carfilzomib, are now available for treatment of myeloma (Kane et al. 2003; Herndon et al. 2013), but remain to be evaluated for autoimmunity.

Mouse models have been exquisite tools for studying the pathomechanisms of diseases and for drug development. However, mice may respond differently from humans to therapies, and show distinct phenotypes from patients with monogenic disorders in orthologous genes. The characterization of PID provides critical molecular insights into key factors mediating TNFR1 signaling. Further studies on PID are required to explore genotype–phenotype correlations and the molecular mechanisms of disease in detail. These studies lay the groundwork for the development of targeted therapies for both rare and common immune and inflammatory diseases. Furthermore, patients with monogenic disorders affecting the TNFR1 pathway help to predict the therapeutic efficacy and side-effects of available therapies targeting TNFR1 signaling.

CONCLUDING REMARKS

TNFR1 signaling is a crucial “command center” controlling immunity, inflammation, and cell death. Dysregulation of these pathways may cause immunodeficiency and/or autoinflammation. Advances in genomic technologies have facilitated the identification of patients with life-threatening PID. The characterization of these patients has provided critical and unexpected insights into the essential role of human TNFR1 signaling in controlling inflammation. The identified candidate genes at the intersection of prosurvival and cell-death pathways have shown that modulation of the TNFR1 pathway can contribute to both severe immunodeficiency and chronic inflammation. Further mechanistic studies in mice and especially advanced human preclinical models will provide critical understanding of imbalanced inflammation and cell death in PID. This knowledge on rare monogenic diseases will help to optimize personalized treatments for children with devastating conditions, but will also prioritize new targets for drug development of common autoimmunity and autoinflammation.

ACKNOWLEDGMENTS

Together with patients suffering from inborn errors of immunity, we have a chance to investigate basic principles of human immunity and autoinflammation. We dedicate this work to all patients with inborn errors of immunity and their families, and thank them for their support of our translational studies. Furthermore, we are grateful to the interdisciplinary medical teams and all global collaboration partners, in particular, the international VEO-IBD consortium. We thank the Care-for-Rare Foundation and The Leona M. and Harry B. Helmsley Charitable Trust for financial support.

Footnotes

Editors: Kim Newton, James M. Murphy, and Edward A. Miao

Additional Perspectives on Cell Survival and Cell Death available at www.cshperspectives.org

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