Top Reads

In this Top Read, Perumal et al. (p. 1123) reported that innate detection of Trypanosoma cruzi infection in mice via cGAS-stimulator of IFN genes (STING) has complex type I IFN (IFN-I)-mediated consequences in different tissues, which partially explains the establishment of chronic parasitic disease. Initial in vivo experiments using wild-type versus cGAS- or STING-deficient mice, and in vitro experiments using isolated macrophages, showed that T. cruzi infection induces a significant, but limited, cGAS–STING-mediated IFN-β response. This IFN-I response initially restricted parasitic growth at the site of infection, but it enhanced parasitic expansion in a second phase. This biphasic parasitic expansion correlated with increased monocyte and decreased neutrophil infiltration to the site, but it was not affected by depletion of inflammatory monocytes or neutrophils. Finally, parasitic growth in the heart, where parasite burden most strongly correlates with clinical disease, was restricted in a STING-dependent manner, whereas parasitic expansion in skeletal muscle was not STING dependent. Together, the data suggest that a STING-dependent IFN-I response limits parasitic growth within the host to limit clinical disease while evading other immune defenses.

In this Top Read, Ma et al. (p. 1099) report that changes to the murine microbiome increase hepatic invariant NKT (iNKT) cell function by regulating the amount of IL-18 produced by CSF-1R⁺ macrophages in the liver. Initial experiments showed that vancomycin treatment increased the frequency of iNKT cells among all other immune cells investigated, and that activation was specific to hepatic, not splenic, iNKT cells. Experiments involving fecal microbial transfer clarified that vancomycin’s iNKT-activating effect is related to the microbiome composition, not to vancomycin itself. Isolated hepatic iNKT cells were not amenable to activation by the same approaches, suggesting a role of the liver environment. Hepatic IL-18 signaling was implicated in iNKT activation using an IL-18–neutralizing Ab and IL-18 knockout mice, and hepatic macrophages were identified as the source of vancomycin-induced IL-18. Depletion of CSF-1R–expressing macrophages and use of CSF-1R knockout mice confirmed that vancomycin-enhanced iNKT activity was mediated specifically by CSF-1R⁺ macrophages. Together, the data suggest that cross-talk between the gut microbiome and the hepatic immune environment could be modulated for therapeutic intervention in immune-mediated liver disease by targeting liver CSF-1R⁺ macrophages.