Top Reads

In this Top Read, Ali et al. (p. 2359) elucidated the mechanism by which second mitochondria-derived activator of caspases memetics (SMs) selectively induce cell death in inflammatory (M1) macrophages. SM treatment resulted in the degradation of cIAP-1, cIAP-2, RIPK-1, and RIPK-3 in M1 macrophages. Torin, a mammalian target of rapamycin inhibitor, rescued M1 macrophages from induced cell death and prevented the degradation of cIAP-2 and RIPK-1/3. Unlike cancer cell lines, endogenous TNF-α and the NF-κB pathway were not critical for SM-induced cell death in human M1 macrophages. Because of the involvement of M1 macrophages in multiple inflammatory diseases, these data provide potential therapeutic targets for M1-associated diseases.

Spondyloarthritis (SpA) is a chronic inflammatory disease defined by joint inflammation, bone destruction, and extra-articular manifestations in the eye, skin, and gastrointestinal tract. Excess TNF is associated with SpA pathogenesis, and mice engineered to overexpress transmembrane TNF (tmTNF) develop symptoms consistent with SpA. In this Top Read, Kaaij et al. (p. 2337) characterized the formation of lymphoid aggregates in tmTNF transgenic (tg) mice to better understand their formation and impact on the immune response in individuals with SpA. The authors detected lymphoid aggregates that resembled ectopic lymphoid structures (ELS) in the bone marrow (BM) of vertebrae and near ankle joints before other SpA symptoms developed, and these ELS contained high endothelial venules, B cells, T cells, and germinal centers. tmTNF tg mice were enriched in T follicular helper cells and T follicular regulatory cells in ELS located at vertebral BM sites and showed a shift toward IgA⁺ plasma cells in the BM, accompanied by higher IgA serum concentrations. ELS formation was heavily dependent on TNF-RI and, together, these findings support a role for TNF in contributing to SpA pathology.

Psoriasis is an autoimmune disease that targets melanocytes, in which the HLA-C*06:02 allele has been linked to autoantigen presentation. In this Top Read, Arakawa et al. (p. 2235) show the endoplasmic reticulum aminopeptidase (ERAP1) can generate the melanocyte autoantigen linked to psoriasis by trimming N-terminal peptide precursors to a length required for HLA-C*06:02 presentation. An ERAP1 haplotype associated with psoriasis risk was more efficient at autoantigen trimming and promoted HLA-C expression and TCR engagement. In contrast, ERAP1 deletion was associated with lower HLA-C cell surface expression. Lesions from psoriasis patients showed elevated levels of ERAP1 and HLA-C on melanocytes, further validating a link between the two molecules and disease pathogenesis. These results define a function for ERAP1 in autoantigen presentation and highlight future areas of study for targeted psoriasis therapeutics.

In humans, increased risk of cardiovascular disease is associated with lymphocyte activation gene-3 (LAG3) deficiency. This deficiency also is characterized by increased TNF-α and decreased IL-10 production by B cells. In this Top Read, Garcia Cruz et al. (p. 2374) describe similar findings in a murine model and expand upon possible mechanisms. Bone marrow–derived DC (BMDC) from Lag3^−/− mice were more immunostimulatory compared with those from WT mice. The mutant BMDC secreted increased amounts of TNF-α, were more metabolically active, and had elevated expression of costimulatory molecules. Following stimulation, Lag3^−/− APCs increased T cell activation and Th1 skewing. Moreover, an increased percentage of adoptively transferred, Ag-specific CD4⁺ T cells produced IFN-γ when challenged in Lag3^−/− mice compared with WT mice. Addition of exogenous IL-10 decreased the metabolic profile of Lag3^−/− BMDC to that of WT BMDC. These findings suggest dendritic cell expression of Lag3 as an important mediator of inflammation.