Background/Purpose: Macrophage Activation Syndrome (MAS) and Hemophagocytic lymphohistiocytosis (HLH) are clinically similar life-threatening hyperinflammatory syndromes, often triggered by viral infection. HLH is associated with cytotoxic impairment (e.g. Perforin deficiency). The causes of MAS remain unknown, but both cytotoxic impairment and elevated Interleukin (IL)-18 may contribute.

Methods: Mice were infected with the typically self-limiting LCMV-Armstrong virus, and assessed for systemic inflammation, serum cytokines, antigen-specific responses, and viral clearance.

Results: Whereas LCMV-infected WT mice developed no outward inflammation, Il18tg mice developed features of MAS (weight loss, splenomegaly, cytopenias, transaminitis, cytokinemia) nearly as severe as Prf1^-/- (Fig 1A). Unlike Prf1^-/-, Il18tg mice had no appreciable impairment in viral clearance and showed normal upregulation of cytotoxic proteins. Consistent with their systemic hyperinflammatory phenotype, Il18tg mice had a larger effector CD8 T-cells response than WT.

Unexpectedly, mice with both hyperinflammatory susceptibility factors (Prf1^-/-;Il18tg mice) were born in Mendelian ratios but quickly developed a spontaneous inflammatory phenotype characterized by weight loss, cytopenias, cytokinemia and hepatosplenomegaly (Fig 1B). Prf1^-/-;Il18tg mice have a concomitant increase in splenic myeloid and activated CD-8 T cells, all consistent with a spontaneous MAS-like phenotype.

Conclusion: Chronic IL-18 promotes systemic hyperinflammation despite apparently normal viral clearance during LCMV infection, consistent with MAS. Spontaneous MAS in Prf1^-/-;Il18tg demonstrates the complementary and non-redundant nature of these mechanisms. It also indicates a homeostatic immunoregulatory function for Perforin. Our data suggest clinical assessment of both pathways could improve targeted treatment in these life-threatening hyperinflammatory disorders.