Macrophages need the enzyme heme oxygenase (HO)-1 to produce the antiviral cytokine IFN-β, according to Tzima et al. on page 1167.
For years, HO-1 was best known for its role in dulling inflammation in part by inhibiting the production of proinflammatory cytokines. Now Tzima and colleagues show that HO-1 can also incite inflammation in the face of viral infection. In response to signals from the TLR3/4 and RIG-I/MDA5 pathways, HO-1 formed a complex with the transcription factor IRF3, allowing IRF3 to migrate to the nucleus and trigger IFN-β and chemokine production. By contrast, HO-1 was not needed for MAPK/NF-kB–mediated cytokine production in response to TLR3/4 signals.
Mice with HO-1–deficient macrophages could not make the IFN-β that they needed to clear a viral infection. Likewise, mice with EAE, an autoimmune disorder similar to multiple sclerosis, were worse off without HO-1 unless they were given an exogenous dose of IFN-β. Until now, researchers had assumed that HO-1 directly suppressed auto-inflammation by generating carbon monoxide, which shuts off the production of inflammatory cytokines.
Whether HO-1's effect on IFN-β synthesis requires its enzymatic activity, or its ability to bind to other proteins, remains to be seen. Learning more about HO-1's role in the antiviral pathway is essential to understanding how it elicits innate responses one moment and quells inflammation the next. Future studies are also needed to determine whether HO-1 is required for the production of IFN-β from other cell types.
