Macrophage re-programming by JAK inhibitors relies on MAFB.

Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3ß, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.

Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB.

Monocyte-derived macrophages contribute to pathogenesis in inflammatory diseases and their effector functions greatly depend on the prevailing extracellular milieu. Whereas M-CSF primes macrophages for acquisition of an anti-inflammatory profile, GM-CSF drives the generation of T cell-stimulatory and pro-inflammatory macrophages. Liver X Receptors (LXRα and LXRß) are nuclear receptors that control cholesterol metabolism and regulate differentiation of tissue-resident macrophages. Macrophages from rheumatoid arthritis and other inflammatory pathologies exhibit an enriched LXR pathway, and recent reports have shown that LXR activation raises pro-inflammatory effects and impairs the acquisition of the anti-Inflammatory profile of M-CSF-dependent monocyte-derived macrophages (M-MØ). We now report that LXR inhibition prompts the acquisition of an anti-inflammatory gene and functional profile of macrophages generated within a pathological environment (synovial fluid from Rheumatoid Arthritis patients) as well as during the GM-CSF-dependent differentiation of human monocyte-derived macrophages (GM-MØ). Mechanistically, inhibition of LXR results in macrophages with higher expression of the v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) transcription factor, which governs the macrophage anti-inflammatory profile, as well as over-expression of MAFB-regulated genes. Indeed, gene silencing experiments on human macrophages evidenced that MAFB is required for the LXR inhibitor to enhance the anti-inflammatory nature of human macrophages. As a whole, our results demonstrate that LXR inhibition prompts the acquisition of an anti-inflammatory transcriptional and functional profile of human macrophages in a MAFB-dependent manner, and propose the use of LXR antagonists as potential therapeutic alternatives in macrophage re-programming strategies during inflammatory responses.

Immunoserologic Detection and Diagnostic Relevance of Cross-Reactive Autoantibodies in Coronavirus Disease 2019 Patients.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, we detected a new immunofluorescence (IF) pattern in serum autoantibody (autoAb) screening of laboratory-confirmed COVID-19 patients. METHODS: The IF pattern was composed of liver and gastric mucosa staining on rat kidney/liver/stomach sections. RESULTS: We describe 12 patients positive for the cross-reactive antibody, compared with a negative group of 43 hospitalized COVID-19 patients, finding association with either neurologic or thrombotic complications. In sequential pre- and post-COVID-19 serum samples, we confirmed autoAb seroconversion. CONCLUSIONS: Our data indicate that autoAb screening in COVID-19 patients may be easily performed by IF and alert for autoreactive-mediated complications such as thrombotic or neurologic events.