The interleukin-1 (IL-1) family cytokines are cytosolic proteins that exhibit inflammatory activity upon release into the extracellular space. These factors are released following various cell death processes, with pyroptosis being a common mechanism. Recently, it was recognized that phagocytes can achieve a state of hyperactivation, which is defined by their ability to secrete IL-1 while retaining viability, yet it is unclear how IL-1 can be secreted from living cells. Herein, we report that the pyroptosis regulator gasdermin D (GSDMD) was necessary for IL-1β secretion from living macrophages that have been exposed to inflammasome activators, such as bacteria and their products or host-derived oxidized lipids. Cell- and liposome-based assays demonstrated that GSDMD pores were required for IL-1β transport across an intact lipid bilayer. These findings identify a non-pyroptotic function for GSDMD, and raise the possibility that GSDMD pores represent conduits for the secretion of cytosolic cytokines under conditions of cell hyperactivation.

Macrophages block tumors' spread Tumors constantly communicate with their surrounding tissue and the immune system. One way tumors likely do this is by secreting extracellular vesicles (tEVs), which can carry bits of the tumor to distant sites in the body. Pucci et al. tracked tEVs in tumor-bearing mice and people and studied how they affect cancer progression. They found that tEVs disseminate through lymph to nearby lymph nodes, where a specialized population of macrophages largely block any further travel. This barrier breaks down, however, as cancer progresses and also in the face of certain therapies. The tEVs can then penetrate lymph nodes, where they interact with B cells that promote further tumor growth. Science , this issue p. 242