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• 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]