Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5/TRAIL-R2

Abstract

To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL (Faslgld/gld)- and soluble FasL (FaslΔs/Δs)-deficient mice, but not in Fas (Faslpr/lpr and Fas–/–)- or membrane FasL (FaslΔm/Δm)-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL–Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced Cx3cl1 transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL–DR5 interaction-mediated CX3CL1–CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL–DR5 interaction promotes inflammation and is a potential therapeutic target.

Comparative single‐cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS‐CoV‐2 infection

“…Interestingly, CD56 NK cells specifically had more preferential interaction pairs in individuals receiving the 1st In‐Vac dose but not in COVID‐19 samples (Figure 7C). CD56 NK expressing FASLG and TNFSF10 interacted with multiple other immune cells expressing TNFRSF10B , TNFRSF1A , FAS , and TNFSF10A 55,56 (Figure 7E, Supporting Information: Figure ). Considering that these molecules have been associated with immunosuppression through promoting apoptosis, 56 this finding suggests that CD56 NK might suppress In‐Vac‐induced immune responses by promoting apoptosis of other immune cells (Supporting Information: Figure ).…”

Role of metalloproteases in the CD95 signaling pathways

“…Interestingly, CD95L might also interact with another TNFR member, DR5 (41). The authors show that, although the CD95L affinity for DR5 was weaker than that for CD95 ((K D was 1.23x10 -12 M for DR5-CD95L versus 6.01x10 -13 M for DR5-TRAIL), CD95L can compete TRAIL for DR5 binding, suggesting that both ligands share a similar interaction region in DR5 (41). More importantly, the CD95L/DR5 interaction has been suggested to promote arthritis severity in a mouse model (i.e., autoantibody-induced arthritis).…”

“…CD95L can be cleaved by several metalloproteases, including MMPs and ADAMs, to release different soluble CD95Ls (s-CD95Ls), which have been reported to induce cell proliferation, migration, survival ( 36 ) but also cell death ( 51 , 59 ). Rendering more complex to predict the biological outcome of s-CD95L, this ligand can also interact with other TNFR members, including as aforementioned, DR5 ( 41 ) or the soluble receptor DcR3 ( 44 ). Despite the complexity of the signaling pathways induced by the different forms of s-CD95L and their implication in the progression of different pathologies including chronic inflammatory disorders and cancers only a limited structural knowledge exists on these s-CD95Ls.…”

“…Thirty years after CD95L cloning, it remains difficult to address what are the MMP/ADAMs responsible for the cytokine shedding, where the protease cleaves m-CD95L and whether the released soluble factor triggers non-apoptotic ( 34 , 41 , 55 , 57 , 78 , 80 , 101 ) or apoptotic outcome ( 51 , 59 , 102 ).…”

Assessment Of Soluble Fas Ligand In Patients With Chronic Myeloid Leukemia

“…Fas-ligand plays a critical role in immune homeostasis by binding to its receptor Fas (CD95) and inducing apoptosis (programmed cell death) [9]. Membrane-bound FasL (mFasL) can be proteolytically cleaved by matrix metalloproteinases (MMPs), generating soluble FasL (sFasL) [10]. Membrane-bound Fas ligand (mFasL) is proapoptotic and proinflammatory but soluble isoform, soluble Fas ligand (sFasL) inhibits the apoptotic and inflammatory activity of mFasL [11].When soluble FasL (sFasL) binds to Fas, cell proliferation, but not apoptosis, is induced [12].…”