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An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19. Author summary: The pathology of severe COVID-19 is associated with massive inflammation and activation of coagulation systems leading to thrombosis and disseminated intravascular coagulation. D-dimer, a degradation product of fibrinogen, accumulates in the blood when thrombus is dissolved. D-dimer is increased following coagulation activation and high levels of D-dimer correlate with poor prognosis in patients with severe disease. Advanced stages of COVID-19 are also associated with high viral loads and presence of Immune Complexes, i. e. viral particles coated with anti-spike protein antibodies. Here we investigated a link between elevated levels of D-dimer, immune complexes, and inflammation in COVID-19 using human monocytes. Our data showed that D-dimer alone induced prostaglandin E2 (PGE2), a final trigger of fever, and inflammatory cytokines, IL-6/IL-8/IL-1β in healthy monocytes. Importantly, PGE2 and cytokines produced by monocytes were significantly increased when monocytes were incubated with D-dimer and immune complexes of SARS CoV-2 viral particles coated with antibodies from COVID-19 patients. These data showed that D-dimer and immune complexes co-amplify the inflammatory responses of monocytes. Understanding the relationship between coagulation cascade and inflammatory response in severe COVID-19 is critical for designing therapies and treatments to improve outcomes of the disease. [ABSTRACT FROM AUTHOR]

• Increase in D-dimer (DD) is associated with coagulopathy in severe COVID-19. • Immune Complexes (IC) of SARS CoV-2 with human plasma anti-spike IgG were formed. • Monocyte-derived M1 and M2 macrophages activated with DD + IC produce PGE2 and IL-6. • DD + IC activated M2 but not M1 macrophages produce TNFα, IL-1β, and IL-10 cytokines. • DD + IC contribute to inflammatory response in lung macrophages in severe COVID-19. Lung macrophages are the first line of defense against invading respiratory pathogens including SARS-CoV-2, yet activation of macrophage in the lungs can lead to hyperinflammatory immune response seen in severe COVID-19. Here we used human M1 and M2 polarized macrophages as a surrogate model of inflammatory and regulatory macrophages and explored whether immune complexes (IC) containing spike-specific IgG can trigger aberrant cytokine responses in macrophages in the lungs and associated lymph nodes. We show that IC of SARS-CoV-2 recombinant S protein coated with spike-specific monoclonal antibody induced production of Prostaglandin E2 (PGE2) in non-polarized (M0) and in M1 and M2-type polarized human macrophages only in the presence of D-dimer (DD), a fibrinogen degradation product, associated with coagulopathy in COVID-19. Importantly, an increase in PGE2 was also observed in macrophages activated with DD and IC of SARS-CoV-2 pseudovirions coated with plasma from hospitalized COVID-19 patients but not from healthy subjects. Overall, the levels of PGE2 in macrophages activated with DD and IC were as follows: M1≫M2>M0 and correlated with the levels of spike binding antibodies and not with neutralizing antibody titers. All three macrophage subsets produced similar levels of IL-6 following activation with DD+IC, however TNFα, IL-1β, and IL-10 cytokines were produced by M2 macrophages only. Our study suggests that high titers of spike or virion containing IC in the presence of coagulation byproducts (DD) can promote inflammatory response in macrophages in the lungs and associated lymph nodes and contribute to severe COVID-19. [ABSTRACT FROM AUTHOR]