Autoinflammation With Infantile Enterocolitis

NLRC4 gain-of-function variants are known to cause various autoinflammatory phenotypes, including familial cold autoinflammatory syndrome (FCAS4) and NLRC4 macrophage activation syndrome (NLRC4-MAS). However, to date, no study has linked NLRC4 gain-of-function variants to systemic lupus erythematosus (SLE). In this study, we identified a novel NLRC4 W655S variant in an SLE patient and her son, who had neonatal lupus complicated with macrophage activation syndrome. Our in vitro experiments demonstrated that the W655S NLRC4 increased ASC speck formation and mature IL-1β secretion compared to the wild-type NLRC4. In addition, the patient had elevated levels of IL-1β and IL-18 in both serum and PBMCs. RNA sequencing showed that NF-κB and interferon signaling pathways were significantly activated in the patient compared to healthy controls. Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. In conclusion, our study identified the NLRC4 W655S variant in a patient with SLE. This is the first report linking inflammasomopathy to monogenic SLE. Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease.

Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1β, IL-1α, and IL-18 and induce a type of inflammatory cell death known as "pyroptosis". Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions.

Dominantly-inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although evidence suggests pyrin-inflammasome activation. Interleukin (IL)-18 is an inflammasome-activated cytokine associated with susceptibility to Macrophage Activation Syndrome (MAS), but its association with PAPA is unclear.

Clinical and genetic data, and serum samples were obtained from patients referred with symptoms concerning for PAPA syndrome. Serum Interleukin-18 (IL-18), IL-18 Binding Protein (IL-18BP), and CXCL9 were assessed by bead-based assay, and free IL-18 was assessed by ELISA.

PSTPIP1-positive PAPA patients' symptoms overlapped with those of mutation-negative PAPA-like patients, but mutation-positive patients had earlier onset and more arthritis. We found uniform elevation of total serum IL-18 in treated PAPA patients at levels nearly as high as NLRC4-associated autoinflammation with infantile enterocolitis (AIFEC) patients and well above levels in most Familial Mediterranean Fever patients. IL-18 elevation in PAPA patients' serum persisted despite fluctuations in disease activity. The soluble IL-18 antagonist IL-18BP was modestly elevated, and PAPA patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of Interferon-gamma activity, but no PAPA patients had histories of MAS.

PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 but not risk for MAS. These findings affect our understanding of the diseases in which IL-18 is over-produced and suggest a link between pyrin-inflammasome activation, IL-18, and autoinflammation without susceptibility to MAS.