Editorial: Systemic Lupus Erythematosus: Death by Fire and ICE?

Most patients with systemic lupus erythematosus (SLE) produce autoantibodies against DNA protein or RNA protein autoantigens, such as U1 small nuclear RNPs (snRNPs) or cytoplasmic small RNPs such as the SSA/Ro 60 autoantigen. Accumulating evidence suggests that the nucleic acid components of these antigens are endogenous adjuvants capable of eliciting chronic inflammatory responses via the innate immune receptors Toll-like receptor 7 (TLR-7) or TLR-9 (1,2). Thus, although strongly associated with autoantibodies, a hallmark of adaptive immunity, SLE increasingly is viewed as a disorder of innate immunity. Along with the TLRs, other cellular sensors, including the nucleotide-binding oligomerization domain (NOD)–like receptors (NLRs), detect exogenous pathogen-associated molecular patterns (PAMPs) or endogenous damage-associated molecular patterns (DAMPs) generated by cell death or stress (Table 1). These innate immune receptors must be tightly regulated to prevent autoimmune or autoinflammatory disorders. Like SLE, systemic autoinflammatory diseases, such as familial Mediterranean fever (FMF) and tumor necrosis factor receptor (TNFR)–associated periodic syndrome, are characterized by recurrent episodes of fever, serositis, arthritis, and skin rashes, but in contrast to SLE, autoantibody production is absent. Autoinflammatory diseases are caused by mutations in the components of inflammasomes, multiprotein assemblies that detect DAMPs and PAMPs, serving as a platform for activation of the protease caspase 1 (also known as interleukin-1 –converting enzyme [ICE]). This leads to the conversion of pro–interleukin-1 (proIL-1) and proIL-18 to their mature forms (3). Caspase 1 can also cleave other less well-defined substrates, leading to pyroptosis, a form of programmed cell death that causes the proinflammatory release of cellular constituents (Figure 1). In contrast, apoptosis resulting from the engagement of Fas by FasL is dependent on caspase 3 and usually noninflammatory in cells of the adaptive immune system (B cells, T cells), although in cells of the innate immune system (macrophages, dendritic cells, neutrophils) Fas signaling can be proinflammatory, stimulating IL-1 and IL-18 production (4,5) (Figure 1). In innate immune cells, the Fas/FasL-dependent, caspase 1–independent, activation of proIL-1 and proIL-18 results from TLR-mediated up-regulation of Fas expression, leading to FADD-dependent activation of caspase 8 and subsequently caspase 3 (4) (Figure 1). There is substantial evidence that lupus is associated with defects in the regulation of cell death and/or the clearance of dead cells (6). Moreover, inflammation and cell death are linked, for example, in the case of the NLRs (also known as NOD-like and leucine-rich repeat receptors), which mediate inflammasome activation (7). Several types of inflammasomes exist, including NLRP1, NLRP3, IPAF, and AIM2 (8). The best studied is the NLRP3 inflammasome, which consists of NLRP3, the adapter protein ASC, and procaspase 1. Mutations of NLRP3 inflammasome components are involved in FMF, Muckle-Wells syndrome, and other autoinflammatory diseases (9). Activation of caspase 1 via the NLRP3 inflammasome requires 2 signals. Signal 1 is delivered via TLR or TNFR signaling, which increases the transcription of proIL-1 and NLRP3. Signal 2 directly activates NLRP3 and is provided by ATP or bacterial toxins (such as staphylococcal -hemolysin) that form pores in the cell membrane, altering the intracellular concentration of Na and K (3). This promotes caspase 1 activation and, consequently, the cleavage of proIL-1 and proIL-18 to mature IL-1 and IL-18, respectively (Figure 1). Until recently, IL-1 was thought to be the most important inflammatory mediaDr. Reeves’ research is supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01-AR-44731). Westley H. Reeves, MD: University of Florida, Gainesville. Address correspondence to Westley H. Reeves, MD, Division of Rheumatology and Clinical Immunology, University of Florida, PO Box 100221, Gainesville, FL 32610-0221. E-mail: whreeves@ufl.edu. Submitted for publication September 3, 2013; accepted in revised form October 3, 2013.