Type I interferon, induced by adenovirus or adenoviral vector infection, regulates the cytokine response to LPS in a macrophage type-specific manner

In mice, adenovirus (Ad)-elicited IFN-ab mediates the overproduction of LPS stimulated cytokines such as TNFa and IL-6. We found that Ad infection also mediates the overproduction of IFN-ab itself and enables its production in splenic marginal zone macrophages, which don’t produce IFN-ab in response to LPS alone. We show the importance of the scavenger receptor MARCO for Ad uptake and cytokine overproduction in vivo, and the differential contribution of infection and rIFN-b to LPS-induced cytokine response in macrophage subsets. TNF-a and IL-6 responses are enhanced in alveolar macrophages and alveolar macrophage-like lines, but downregulated in bone-marrow-derived and peritoneal macrophages, which correlates with the absence and presence of the anti-inflammatory IL-10 response. The IFN-ab response to LPS is enhanced in all four macrophage types. In Ad-infected mice, the rough LPS chemotype-induced TNF-a production partially depends on the LPS co-receptor CD14, while the IL-10 response is independent of CD14. The IFN-ab responses are strictly CD14-dependent, and partly IRF-3-independent. Upregulated TNF-a and IL-6, and downregulated IL-10 responses to LPS were also found in human blood treated ex vivo with SARS-CoV-2 adenovirus vaccine or rIFN-b. The altered reactivity of cytokine-producing cells to the ubiquitously present LPS could promote adverse effects of viral infection or vaccination.