Inflammation Unrestrained by SIRPα Induces Secondary Hemophagocytic Lymphohistiocytosis Independent of IFN-γ

A hallmark of secondary hemophagocytic lymphohistiocytosis (sHLH), a severe form of cytokine storm syndrome, is the emergence of overactivated macrophages that engulf healthy host blood cells (i.e., hemophagocytosis) and contribute to the dysregulated inflammation-driven pathology. In this study, we show that depleting SIRP alpha (SIRP alpha(-/-)) in mice during TLR9-driven inflammation exacerbates and accelerates the onset of fulminant sHLH, in which systemic hemophagocytosis, hypercytokinemia, consumptive cytopenias, hyperferritinemia, and other hemophagocytic lymphohistiocytosis hallmarks were apparent. In contrast, mice expressing SIRP alpha, including those deficient of the SIRP alpha ligand CD47 (CD47(-/-)), do not phenocopy SIRP alpha deficiency and fail to fully develop sHLH, albeit TLR9-inflamed wild-type and CD47(-/-) mice exhibited hemophagocytosis, anemia, and splenomegaly. Although IFN-gamma is largely considered a driver of hemophagocytic lymphohistiocytosis pathology, IFN-gamma neutralization did not preclude the precipitation of sHLH in TLR9-inflamed SIRP alpha(-/-) mice, whereas macrophage depletion attenuated sHLH in SIRP alpha(-/-) mice. Mechanistic studies confirmed that SIRP alpha not only restrains macrophages from acquiring a hemophagocytic phenotype but also tempers their proinflammatory cytokine and ferritin secretion by negatively regulating Erk1/2 and p38 activation downstream of TLR9 signaling. In addition to TLR9 agonists, TLR2, TLR3, or TLR4 agonists, as well as TNF-alpha, IL-6, or IL-17A, but not IFN-gamma, similarly induced sHLH in SIRP alpha(-/-) mice but not SIRP alpha(+) mice. Collectively, our study suggests that SIRP alpha plays a previously unappreciated role in sHLH/cytokine storm syndrome pathogenesis by preventing macrophages from becoming both hemophagocytic and hyperactivated under proinflammation.