SLAMF7 engagement super-activates macrophages in acute and chronic inflammation

Simmons, Daimon P.; Nguyen, Hung N.; Gomez-Rivas, Emma; Jeong, Yunju; Chen, Antonia F.; Lange, Jeffrey K.; Dyer, George S.; Blazar, Philip; Earp, Brandon E.; Rao, Deepak A.; Kim, Edy Y.; Brenner, Michael B.

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 super-activated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-α following SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients, but in gut macrophages from active Crohn’s disease patients and lung macrophages from severe COVID-19 patients. This suggests a central role for SLAMF7 in macrophage super-activation with broad implications in pathology.