It is suggested that in diseases caused by insufficient TNFAIP3/A20 activity, autoantibodies may reflect a downstream consequence of disease rather than a causative driver, suggesting autoinflammatory rather than autoimmune pathology.
Abstract
Feedback mechanisms regulate immune activation and prevent excessive tissue damage. TNFAIP3, also known as A20, serves as a crucial brake on inflammation, and mutations or haploinsufficiency of this gene are linked to diseases characterized by inappropriate inflammation. In this study, we document highly conserved patterns of cell type-specific gene expression, regulation, and induction of TNFAIP3, and employ transgenic and gnotobiotic mouse models to investigate how adaptive immunity and the gut microbiome contribute to pathology arising from impaired A20 function. Contrary to our expectations, systemic inflammation resulting from Tnfaip3 deficiency in CD11c (Itgax)-expressing cells developed independently of autoreactive antibodies, B cells, and T cells. The microbiome also proved dispensable for disease manifestations in these models. These findings suggest that in diseases caused by insufficient TNFAIP3/A20 activity, autoantibodies may reflect a downstream consequence of disease rather than a causative driver, suggesting autoinflammatory rather than autoimmune pathology. These insights carry therapeutic implications for the treatment of TNFAIP3-associated diseases.
The NF-κB signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-κB subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying previously unreported heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-κB signaling was intact, but induction of inhibitory regulators such as IκBα and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-κB activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-κB feedback control to unchecked inflammation and inflammatory cell death.
Nadja Lucas, S. Weidler, Antonia Eicher et al.· JCI Insight· 0 citations
The NLRP3 inflammasome is a central regulator of innate immunity and inflammation, but its functions extend beyond a simple pro-inflammatory role. Increasing evidence indicates that the biological consequences of NLRP3 activation are highly context-dependent, with protective or pathogenic effects determined by cellular composition, tissue microenvironment, and disease stage. In this review, we examine NLRP3 biology across three interconnected dimensions: cellular context, including immune and non-immune compartments; microenvironmental context, including infectious versus sterile inflammation and tissue repair versus tissue damage; and disease context, including stage- and time-dependent functional shifts. We further discuss three major determinants of NLRP3 output: cytokine bias between IL-1β and IL-18, cell-fate decisions between pyroptosis and survival, and epigenetic programming of inflammasome-responsive states. Using representative disease settings such as cancer, inflammatory bowel disease, and autoimmune disorders, we illustrate how similar NLRP3 activation can lead to divergent biological outcomes. We also discuss the therapeutic implications of this plasticity, arguing that effective intervention will require context-selective rather than universal inhibition. A more precise understanding of NLRP3 context dependence may support rational trial design, biomarker development, future patient-stratification frameworks, and more biologically informed therapeutic strategies in NLRP3-related diseases.
Shuo Liu, Xun Liu, Jing Hu et al.· Journal of Translational Med...· 0 citations
TNF-like cytokine 1A (TL1A) and its receptor DR3 form a key regulatory axis within mucosal immunity, integrating signals that promote Th1/Th17 responses, modulate innate lymphoid cells, and influence epithelial repair. Beyond inflammation, TL1A directly activates intestinal fibroblasts and contributes to extracellular matrix deposition, positioning the TL1A-DR3 pathway as a central driver of both chronic inflammation and fibrosis in inflammatory bowel disease (IBD). Genetic variants in TNFSF15, which encodes TL1A, further support a causal role, linking increased TL1A expression with susceptibility to Crohn's disease, ulcerative colitis, and fibrostenotic complications. Recent clinical trials of TL1A-neutralizing antibodies, including afimkibart, tulisokibart, and duvakitug, have demonstrated encouraging efficacy and safety in moderate-to-severe IBD, with emerging biomarker strategies suggesting potential for personalized treatment. Collectively, current evidence highlights TL1A blockade as a promising dual-pathway therapeutic approach targeting inflammation and fibrotic remodeling, with ongoing studies expected to define its long-term impact on disease modification.
Kozo Tsuruta, S. Yoshioka, H. Takedatsu· The Kurume Medical Journal· 0 citations
Inflammatory bowel disease (IBD) is characterized by unresolved mucosal inflammation driven mainly by TNFα and/or IFNγ. While anti-TNFα biologics are a clinical mainstay, therapeutic resistance remains a significant hurdle. The molecular mechanisms that sustain inflammation in anti-TNFα non-responders are not fully understood. In human colon biopsies, we identified significant upregulation of the deubiquitinase OTUD5 in non-responders compared to responders, suggesting its involvement in therapy resistance. Using an intestinal epithelial cell (IEC)-specific Otud5 knockout mouse model, we show that Otud5 deficiency significantly alleviated the IFNγ-dependent colitis induced by dextran sulfate sodium (DSS), as evidenced by reduced weight loss and diminished infiltration of Ly6C+ inflammatory monocytes. Mechanistically, IFNγ induces OTUD5 expression through a non-transcriptional mechanism; in turn, OTUD5 stabilizes STAT1 and STAT2 by preventing their ubiquitination and subsequent degradation. This sustains IFNγ-ISGF3 signaling, which directly drives the expression of CCL8, a critical chemokine for monocyte recruitment. Targeting this pathway with a newly identified small-molecule inhibitor, CT1170, which exhibits potent activity against OTUD5, blocked the IFNγ-ISGF3-CCL8 axis, halted colitis progression, and suppressed colitis-elicited tumorigenesis. These findings were validated in human IBD organoids, where CT1170 effectively disrupted IFNγ-driven inflammatory signaling.
Huiyuan Guan, Changzhou Cai, Jie-xin Wang et al.· Journal of Biological Chemis...· 0 citations
Inflammasome activation is an essential component of innate immunity. Recently, its role in regulating various T cell responses has also become increasingly recognized. Interestingly, we found increased expression of Nlrp3 and many genes associated with the NLRP3 inflammasome pathway in intestinal regulatory T cells (Tregs) from mice with autoimmune-mediated inflammation. This unexpected finding of a pro-inflammatory pathway upregulated in a cell type typically known for suppressing immune responses called for further investigation.
We developed a new mouse model with a Treg-specific deletion of Nlrp3 and subjected the mice to a variety of disease models of intestinal inflammation. We then performed RNA-seq on NLRP3-sufficient and NLRP3-deficient intestinal Tregs isolated from a similar inflammatory environment to gain mechanistic insights. To further characterize the subset of intestinal Tregs that upregulated Nlrp3, we used the novel PrimeFlow RNA Assay.
In multiple disease models, loss of NLRP3 in Tregs led to elevated Th17 responses accompanied by reduced Th1 responses despite similar Treg frequencies and comparable levels of Foxp3 expression. Mechanistically, NLRP3 likely confers Treg suppressor function against Th17 cells through driving the production of molecules that antagonize IL-1 signaling.
Collectively, we demonstrate a previously underappreciated anti-inflammatory role of NLRP3 in Tregs in controlling Th17 responses in the intestines. Ultimately, our work should guide effective therapies for intestinal disorders where the anti-inflammatory vs. proinflammatory role of NLRP3 is still debated.
NIDDK F31 2023-2025 and Biolegend Fellow in Immunology 2021-2022
Immune Response Regulation: Cellular Mechanisms (IRC)
Rasika Patkar, Justin Yip, Chia-Hao Lin et al.· Journal of Immunology· 0 citations
It is suggested that bidirectional disruptions to normal LRRK2 function break immune homeostasis and immune cell function should be carefully considered when targeting LRRK2 kinase activity in patients with PD.
Robert C. Sharp, Shannon C. Wall, Jordan C. Follet et al.· bioRxiv· 0 citations