Unmasking an agent of inflammatory anemia: Infectious and autoimmune diseases are associated with anemia and thrombocytopenia. A severe form of inflammatory cytopenia called macrophage activation syndrome (MAS) may occur during rheumatological disorders and viral infections. Akilesh et al. show that monocyte recognition of self- or pathogen-derived nucleic acids via Toll-like receptors 7 and 9 (TLR7 and TLR9) drives MAS-like disease in mice. TLR7 or TLR9 signaling in monocytes causes these cells to differentiate into inflammatory hematophagocytes (iHPCs), which are similar to but distinct from red pulp macrophages. Preventing iHPC differentiation by depleting monocytes relieves MAS-like symptoms. When mice were subjected to a model of malarial anemia, MyD88- and endosomal TLR-dependent iHPC differentiation also occurred. Thus, iHPCs may play a role in both MAS-driven and malarial anemia, as well as thrombocytopenia. Science , this issue p. eaao5213

Genetic variants within or near the interferon regulatory factor 5 ( IRF5 ) locus associate with systemic lupus erythematosus (SLE) across ancestral groups. The major IRF5 -SLE risk haplotype is common across populations, yet immune functions for the risk haplotype are undefined. We characterized the global immune phenotype of healthy donors homozygous for the major risk and nonrisk haplotypes and identified cell lineage–specific alterations that mimic presymptomatic SLE. Contrary to previous studies in B lymphoblastoid cell lines and SLE immune cells, IRF5 genetic variants had little effect on IRF5 protein levels in healthy donors. Instead, we detected basal IRF5 hyperactivation in the myeloid compartment of risk donors that drives the SLE immune phenotype. Risk donors were anti-nuclear antibody positive with anti-Ro and -MPO specificity, had increased circulating plasma cells and plasmacytoid dendritic cells, and had enhanced spontaneous NETosis. The IRF5 -SLE immune phenotype was conserved over time and probed mechanistically by ex vivo coculture, indicating that risk neutrophils are drivers of the global immune phenotype. RNA-Seq of risk neutrophils revealed increased IRF5 transcript expression, IFN pathway enrichment, and decreased expression of ROS pathway genes. Altogether, the data support that individuals carrying the IRF5 -SLE risk haplotype are more susceptible to environmental/stochastic influences that trigger chronic immune activation, predisposing to the development of clinical SLE.

The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain–, and retinoic acid–inducible gene I–like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type– and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-α production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser⁴⁶²)IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease.

T follicular helper (Tfh) and T follicular regulatory cells (Tfr) are required for antibody production and are dysregulated in SLE. Genetic variants within or near interferon regulatory factor 5 (IRF5) are associated with SLE risk. We previously reported higher plasma cells and autoantibodies in healthy IRF5-SLE homozygous risk carriers. Here, we report the dysregulation of circulating Tfh and Tfr in both SLE patients and presymptomatic IRF5-SLE homozygous risk carriers.