Fas/CD95 Signaling Pathway in Damage-Associated Molecular Pattern-Sensing Receptors: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Patrick Legembre.

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K). Recent data suggest that CD95 can also activate pattern recognition receptors (PRRs) known to sense damage-associated molecular patterns (DAMPs) such as DNA debris and dead cells. This activation might contribute to the pro-inflammatory role of CD95 and favor cancer development or severity of chronic inflammatory and auto-immune disorders.

  • apoptosis
  • auto-immunity
  • CD95
  • inflammasome
  • necroptosis
  • pyroptosis
  • sting

1. Introduction

Although CD95 (Fas) has long been viewed as the death receptor prototype, only involved in the induction of the apoptotic signaling pathway, more recent and accumulating evidence point out that this transmembrane receptor contributes to chronic inflammatory disorders and cancer by inducing non-apoptotic signaling pathways [1,2][1][2].

2. CD95 and DAMP-Sensor-Mediated Pathologies

2.1. Genetic Mutations in CD95 and DAMP Sensors and Chronic Inflammatory Diseases

2.1.1. CD95-Associated Genetic Disorders

In humans, CD95 mutation leads to the development of a disease called auto-immune lymphoproliferative syndrome or ALPS, also known as Canale–Smith syndrome [3]. ALPS involves the development of early onset polyclonal lymphoproliferation (splenomegaly, adenopathy) associated with expansion of a population of aberrant double-negative B220+CD3+TCRαβ+CD4−CD8− T cells. To qualify as ALPS, the evolution of the disease must be superior to 6 months and with exclusion of a secondary etiology for the lymphoproliferation (hematological malignancies or solid cancers, for example) [4,5][4][5]. This cardinal presentation is associated with mutation of CD95, CD95L, or caspase 10, a defect in lymphocyte proliferation, autoimmune cytopenia (mainly autoimmune hemolytic anemia and immune thrombocytopenic purpura), augmentation of Immunoglobulin A and G titers, associated with elevated dosage of B12 vitamin, augmentation of IL-10 or IL-18 and an increase in soluble-CD95L in patient serum. Of note, ALPS present an increased risk of hematological malignancies, which can complicate its diagnosis [6]. ALPS are divided into five subtypes, showing mutations in CD95, CD95L, or caspase-10 (see Table 1). Although most of the ALPS patients exhibit CD95 mutations, when Oliveira et al. revised the ALPS classification in 2010, lymphoproliferative disorders showing no mutations in CD95, CD95L, or caspase 10 were also classified as ALPS disorders (i.e., caspase 8, NRAS/KRAS, or SH2D1a mutations). In addition, Dianzani Autoimmune Lymphoproliferative Disease (DALD) was also reported as an ALPS-related disorder even though still no genetic defect was identified [4,5][4][5].
Table 1.
Auto-immune lymphoproliferative syndrome (ALPS) classification.

ALPS Type

Mutation Type

ALPS-FAS

CD95 germline homo- or heterozygous mutation
9]. These DAMP sensors have been implicated in several inflammatory diseases, on a spectrum ranging from autoimmune polygenic phenotypes such as in systemic lupus erythematosus, rheumatoid arthritis or Crohn’s disease, to monogenic autoinflammatory disorders [10]. In these monogenic autoinflammatory syndromes, enhanced activation of the inflammasome pathway due to genetic mutations (i.e., nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain 1/NLRP1, NLRP3, NLR family CARD domain-containing protein 4/NLRC4 or Pyrin), leads to common clinical phenotypes involving fever, skin rash, or dermatologic lesions and systemic symptoms (such as arthralgia or arthritis for example), associated with elevated inflammatory markers in the blood of affected patients [11]. For instance, NLRP1 mutations lead to NLRP1-associated Auto-Inflammation with Arthritis and Dyskeratosis (NAIAD) [12] and NLRC4 gain-of-function mutations triggers Syndrome of enterocolitis and Autoinflammation associated with mutation in NLRC4 (SCAN4) [13] or recurrent Macrophage Activation Syndrome (MAS) [14], (see Table 2).
Table 2.
DAMP-sensor-associated genetic disorders.

DAMP-Sensor Mutation

Mutation Type

Autoinflammatory Disorder

NLRP1

Loss of function

NAIAD

ALPS-sFAS

CD95 somatic mutation

NLRP3

Gain of function

CAPS = NOMID, FCAS, MWS

ALPS-FASLG

CD95L germline mutation

ALPS-CASP10

Caspase 10 germline mutations

ALPS-U

ALPS phenotype with no known-ALPS mutation
Similarly, CD95 (Lpr and Lprcg mice) or CD95L (Gld) mutations in mice lead to a similar phenotype with aberrant T cell proliferation and lymphoproliferation, but also arthritis and early death from acute glomerulonephritis. These mice exhibit the development of autoantibodies, such as those found in Systemic Lupus Erythematosus (SLE) patients, and have led to their use as a model for SLE physio-pathological studies. However, this autoantibody development in CD95-mutated mice represents a striking difference with the human pathology in which autoantibodies do not represent a common clinical feature of human ALPS [7].

2.1.2. DAMP-Sensor-Associated Genetic Disorders

DAMP are non-infectious triggers of the immune system released by dying or damaged cells [8] and detected by various membrane-bound or intracellular sensors, notably through a cytosolic complex called inflammasome [

NLRC4

Gain of function

SCAN4, MAS

Pyrin

Gain of function of MEFV or loss of function of MVK

FMF, HIDS, PAAND

PSTPIP1

Loss of function

PAPA
CAPS: Cryopyrin-Associated Periodic Syndrome; DAMP: Damage-Associated Molecular Patterns; FCAS: Familial Cold Autoinflammatory Syndrome; FMF: Familial Mediterranean Fever; HIDS: Hyper-IgD Syndrome; MAS: Macrophage Activation Syndrome; MVK: Mevalonate Kinase; MWS: Muckle-Wells Syndrome; NLRP: Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain; NLRC4: NLR Family CARD Domain Containing 4; NOMID: Neonatal-Onset Multisystem Inflammatory Disease; PAAND: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis; PAPA, Pyogenic sterile Arthritis, Pyoderma gangrenosum, and Acne; PSTPIP1: Proline Serine Threonine Phosphatase-Interacting Protein 1; SCAN4: Syndrome of enterocolitis and Autoinflammation associated with mutation in NLRC4; TNFR1: TNF-Receptor-1; TRAPS: TNF-Receptor-Associated Periodic Syndrome. Diseases induced by mutation in NLPR3 correspond to a group named Cryopyrin-Associated Periodic Syndrome (CAPS). CAPS represents a spectrum of related clinical phenotypes due to sporadic or autosomal dominant mutations in NLPR3 and previously described as three distinct diseases: NOMID (Neonatal-Onset Multisystem Inflammatory Disease, also known as Chronic Infantile Neurological Cutaneous Articular syndrome or CINCA), FCAS (Familial Cold Autoinflammatory Syndrome) and MWS (Muckle-Wells Syndrome) [15]. Diseases associated with Pyrin mutations encompass the Familial Mediterranean Fever (FMF), which is due to a gain-of-function mutation in the MEFV gene encoding Pyrin [16]. S242R and E244K mutations in pyrin sequence disrupt its interaction with the regulatory 14-3-3 protein and leads to the inflammasome activation and the constitutive IL1β and IL-18 secretion in a monogenic pathology called Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) [17]. Additionally, the related PAPA syndrome (for Pyogenic sterile Arthritis, Pyoderma gangrenosum, and Acne) implicates mutations (A230T or E250Q) in the phosphatase PSTPIP1 that better interact with Pyrin promoting IL-1β and IL-18 secretion [18]. All these DAMP-sensor mutations and their associated diseases are summarized in Table 2. Interestingly, the high systemic inflammatory symptoms/systemic clinical manifestations observed with these pathologies seem to be shared with those observed in mice exhibiting an uncleavable caspase-8 and deficient for the necroptotic factors mixed-lineage kinase domain-like protein (MLKL) or receptor-interacting protein kinase 3 (RIPK3) [19]. Indeed, these mice die to a systemic and exacerbated inflammatory response that can be abrogated by the elimination of one CD95L allele [19], suggesting that a molecular link might exist between CD95 stimulation and the inflammasome activation in certain pathophysiological contexts.

3. CD95/Fas

CD95 is a member of the tumor necrosis family receptors (TNF-Rs) and it is the prototype receptor to study the apoptotic signaling pathway. TNF-Rs are devoid of any enzymatic activity and necessitate protein-protein interactions (PPIs) to recruit enzymes such as proteases, kinases, and ubiquitin ligases to implement dynamic and complex signaling pathways. At the plasma membrane, CD95 auto-aggregates as homotrimer independently of its natural ligand, CD95L (also known as FasL or CD178) [20,21,22,23][20][21][22][23]. This trimeric structure is mandatory to implement cell death and rapidly forms larger signaling platforms in the presence of its natural ligand [20]. CD95 engagement induces the recruitment of the adaptor protein FADD, which in turn aggregates pro-caspase-8 in a complex-designated death-inducing signaling complex (DISC) [24]. Beyond DISC formation and induction of the apoptotic signal, FADD and caspase-8 contribute to different complexes involved in the induction of necroptosis or pyroptosis (discussed below). The switch between apoptosis and necroptosis has been discussed previously [25]. Briefly, ubiquitination of RIPK1 is a pivotal post-translational modification for the induction of the TNF-R1-mediated NF-κB activation [26,27][26][27] and its deubiquitination leads to the induction of cell death. The deubiquitinated RIPK1 is released from the death receptor and recruits TRADD, Fas-associated death domain (FADD), pro-caspase-8, and the long isoform of FLICE-like inhibitory protein (FLIPL) to trigger apoptosis [28]. In this complex, the caspase-8-mediated RIPK1 cleavage extinguishes the kinase activity. Degradation of c-IAP1 and c-IAP2 prevents the K63 ubiquitination of RIPK1 [29] and promotes the formation of another cellular complex in which FADD, pro-caspase-8, and FLIPL associate to trigger apoptosis. When caspase-8 is inactivated in these two complexes, the necrosome is formed. RIPK1 associates with RIPK3 to form this complex, in which RIPK3 phosphorylates MLKL to promote its plasma membrane distribution and the induction of necrosis [30,31,32][30][31][32]. Although CD95 engagement displays a broad range of cellular outcomes [33], whether such complexes occur in a CD95-dependent manner remains to be elucidated. Interestingly, the elimination of FADD or caspase-8 in mice does not lead to hyperplasia but instead is responsible for embryonic lethality, and these mice can survive post weaning when a double-ko mouse is realized with one of the necroptosis-mediating genes, RIPK3 [34,35][34][35] or MLKL [36] pointing out the tight control of the necroptotic machinery by the apoptotic one. Interestingly, caspase-8−/−/RIPK3−/− or caspase-8−/−/MLKL−/− double-ko mice develop hyperinflammation and lymphadenopathy, a phenotype resembling that observed in CD95-deficiency Lpr mice strongly suggesting that these factors control an additional mechanism in which CD95 could be involved too.

4. Inflammation

Inflammation after infection or injury relies on the detection of pathogen-associated and damage-associated molecular patterns (PAMPs/DAMPs). Examples of sterile DAMPs includes cholesterol crystals (atherosclerosis), β-amyloid (Alzheimer’s), islet amyloid polypeptide, ceramide, saturated fatty acids (type II diabetes), asbestos, silica dioxide (pulmonary fibrotic disorders), and monosodium urate (gout) [8,94][8][37]. Pattern recognition receptors (PRRs) translate the cell stress into proinflammatory signals. The cytosolic PAMPs/DAMPs activate inflammasome, which in turn induces caspase-1 activity leading to the maturation of interleukin-1β (IL-1β) and IL-18 [95,96][38][39]. Inflammasome can also induce pyroptosis by cleaving gasdermin D (GsdmD) [97,98][40][41]. GsdmD forms plasma membrane pores responsible for the induction of cell death and the release of mature IL-1β and IL-18 [99,100][42][43] (Figure 1). The signal 2 activating NLRP3 is diverse and includes mitochondrial reactive oxygen species (ROS), potassium efflux, and/or chloride influxes [101][44] (Figure 2), pointing out that NLRP3 is a sensor for a broad spectrum of cellular disturbances.
Figure 1. CD95 stimulation and potential links with inflammasome activation. At least three molecular complexes could occur upon CD95 engagement to trigger either apoptosis (pink circle), inflammation (green circle), or necrosis (blue circle). Apoptotic and necroptotic complexes control each other and the inflammatory complex (red lines). Necroptosis and pyroptosis signaling pathways lead to the break of the plasma membrane. IAPs also control an additional complex and these members are known to participate in the TNF-R-mediated signaling pathway. The NLRP3 inflammasome, which is activated by signal 1 + 2 is depicted. (GsdmD = Gasdermin D).
Figure 2. Representation of ion channels involved in the inflammasome activation. Different plasma membrane or endoplasmic reticulum ion channels have been involved in ion fluxes (black arrows) responsible for the signal 2 activating the inflammasome.

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