A single sugar makes all the difference: Antibodies are divided into several classes based on their nonvariable tail (Fc) domains. These regions interact with disparate immune cell receptors and complement proteins to help instruct distinct immune responses. The Fc domain of immunoglobulin G (IgG) antibodies contains a conserved N-linked glycan at position 297. However, the particular glycan used at this position is highly variable. IgG lacking core fucosylation at this position initiates enhanced antibody-dependent cellular cytotoxicity by increased affinity to the Fc receptor FcRIIIa. Larsen et al. report that COVID-19 patients with severe symptoms have increased levels of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG afucosylation compared with patients with mild disease. These findings suggest that treatment of COVID-19 patients with fucosylated anti–SARS-CoV-2 antibodies may circumvent pathologies associated with severe COVID-19. Science , this issue p. eabc8378

High titers and low fucosylation of human anti–spike protein IgG promote alveolar macrophage activation and inflammation.

The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

Afucosylated IgG1 responses have only been found against membrane-embedded epitopes, including anti-S in SARS-CoV-2 infections. These responses, intrinsically protective through enhanced FcγRIIIa binding, can also trigger exacerbated pro-inflammatory responses in severe COVID-19. We investigated if the BNT162b2 SARS-CoV-2 mRNA also induced afucosylated IgG responses. Blood from vaccinees during the first vaccination wave was collected. Liquid chromatography-Mass spectrometry (LC-MS) was used to study anti-S IgG1 Fc glycoprofiles. Responsiveness of alveolar-like macrophages to produce proinflammatory cytokines in presence of sera and antigen was tested. Antigen-specific B cells were characterized and glycosyltransferase levels were investigated by Fluorescence-Activated Cell Sorting (FACS). Initial transient afucosylated anti-S IgG1 responses were found in naive vaccinees, but not in antigen-experienced ones. All vaccinees had increased galactosylated and sialylated anti-S IgG1. Both naive and antigen-experienced vaccinees showed relatively low macrophage activation potential, as expected, due to the low antibody levels for naive individuals with afucosylated IgG1, and low afucosylation levels for antigen-experienced individuals with high levels of anti-S. Afucosylation levels correlated with FUT8 expression in antigen-specific plasma cells in naive individuals. Interestingly, low fucosylation of anti-S IgG1 upon seroconversion correlated with high anti-S IgG levels after the second dose. Here, we show that BNT162b2 mRNA vaccination induces transient afucosylated anti-S IgG1 responses in naive individuals. This observation warrants further studies to elucidate the clinical context in which potent afucosylated responses would be preferred. LSBR1721, 1908; 10.13039/501100001826 ZonMW 10430012010021, 09150161910033, 10430012010008; DFG398859914, 400912066, 390884018; PMI; DOI4-Nr. 3; H2020-MSCA-ITN 721815.

Macrophages are heterogeneous leukocytes regulated in a tissue- and disease-specific context. While in vitro macrophage models have been used to study diseases empirically, a systematic analysis of the transcriptome thereof is lacking. Here, we acquired gene expression data from eight commonly-used in vitro macrophage models to perform a meta-analysis. Specifically, we obtained gene expression data from unstimulated macrophages (M0) and macrophages stimulated with lipopolysaccharides (LPS) for 2–4 h (M-LPS_early), LPS for 24 h (M-LPS_late), LPS and interferon-γ (M-LPS+IFNγ), IFNγ (M-IFNγ), interleukin-4 (M-IL4), interleukin-10 (M-IL10), and dexamethasone (M-dex). Our meta-analysis identified consistently differentially expressed genes that have been implicated in inflammatory and metabolic processes. In addition, we built macIDR, a robust classifier capable of distinguishing macrophage activation states with high accuracy (>0.95). We classified in vivo macrophages with macIDR to define their tissue- and disease-specific characteristics. We demonstrate that alveolar macrophages display high resemblance to IL10 activation, but show a drop in IFNγ signature in chronic obstructive pulmonary disease patients. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but acquired LPS-activation features in diabetic-obese patients. Rheumatoid arthritis synovial macrophages exhibit characteristics of IL10- or IFNγ-stimulation. Altogether, we defined consensus transcriptional profiles for the eight in vitro macrophage activation states, built a classification model, and demonstrated the utility of the latter for in vivo macrophages.

Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.