Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn’s disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.
SLAMF7 is up-regulated on macrophages in inflamed tissues and drives superactivation in inflammatory human disease.
Macrophages produce inflammatory cytokines that stimulate immune responses against pathogens, but excessive or chronic activation in inflammatory diseases can lead to tissue damage. By profiling synovial macrophages, Simmons et al. found that SLAM family member (SLAMF7) was elevated in patients with rheumatoid arthritis (RA) compared with less inflammatory osteoarthritis and could be induced by IFN-γ. Signaling through SLAMF7 in macrophages stimulated a cascade of inflammatory cytokine production that was further amplified by autocrine TNF. Macrophages from patients with inflammatory bowel disease or COVID-19 also expressed a transcriptional profile of dysfunctional SLAMF7-driven activation that was correlated with disease activity, demonstrating that SLAMF7-associated macrophage activation occurs during both acute and chronic human inflammatory diseases.