Type I interferons (IFN-I) are central mediators of the mammalian antiviral defense. However, in contrast to the critical role in antiviral defense, excessive IFN-I signaling can drive serious inflammatory pathology in a wide range of autoimmune diseases and nonviral infections. A common feature of pathological IFN-I responses is the excessive accumulation and activation of neutrophils. In these contexts, neutrophils are commonly viewed as responders to IFN-I, where IFN-I secreted from other cell types can promote neutrophil accumulation, swarming, and extracellular trap (NET) release. One example is the association of IFN-I signaling in neutrophils to increased susceptibility to Mycobacterium tuberculosis infection. This talk will highlight our molecular dissection of the association of IFN-I signaling and neutrophils in regulating the inflammatory responses to M. tuberculosis infection and how we can target these processes with new strategies to treat tuberculosis.