Antibody-opsonized extracellular traps reprogram macrophage responses and suppress their T cell-directed pro-inflammatory activity

Fc domain-dependent ET phagocytosis by both macrophage subsets is significantly enhanced when ETs are opsonized with an anti-citrullinated histone H2A and H4 monoclonal antibody. Opsonized ETs upregulate expression of genes encoding negative regulators of Mitogen-Activated Protein Kinase (MAPK) signaling and reduce expression of genes encoding pro-inflammatory cytokines and chemokines. Exposure to antibody-opsonized ETs following macrophage activation with LPS and IFN-γ suppresses the T cell-directed features of pro-inflammatory macrophages with reduced surface expression of CD80 and CD86 and decreased secretion of IL-12 and CXCL9.

In inflammation-resolving macrophages antibody-opsonized ETs attenuate MAPK-dependent Toll-like receptor responses and inhibit CXCL9 and CXCL10 production while enhancing IL-10 secretion. Together, these findings describe the pro-inflammatory impact of ET exposure on macrophages and delineate a previously unrecognized regulatory axis by which antibodies targeting ET components reprogram macrophage responses across distinct subsets to suppress their T cell-directed pro-inflammatory activity, highlighting a promising therapeutic strategy for ameliorating ET-driven inflammation.