Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.

Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the BCL2 family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.

Macrophages play a major role in the pathogenesis of atherosclerosis. Many studies have shone light on the different phenotypes and functions that macrophages can acquire upon exposure to local cues. The microenvironment of the atherosclerotic plaque contains a plethora of macrophage-controlling factors, such as cytokines, oxidised lowdensity lipoproteins and cell debris. Previous research has determined macrophage function within the plaque mainly by using immunohistochemistry and bulk analysis. The recent development and rapid progress of single-cell technologies, such as cytometry by time of flight and single-cell RNA sequencing, now enable comprehensive mapping of the wide range of cell types and their phenotypes present in atherosclerotic plaques. In this review we discuss recent advances applying these technologies in defining macrophage subsets residing in the atherosclerotic arterial wall of mice and men. Resulting from these studies, we describe three main macrophage subsets: resident-like, proinflammatory and anti-inflammatory foamy TREM2 hi macrophages, which are found in both mouse and human atherosclerotic plaques. Furthermore, we discuss macrophage subset-specific markers and functions. More insights into the characteristics and phenotype of immune cells within the atherosclerotic plaque may guide future clinical approaches to treat disease.