Beyond the grave: When is cell death critical for immunity to infection?

• Regulated cell death (RCD) can impact on immunity to microbes via multiple mechanisms.
• Manipulation of RCD shows RCD can have both beneficial and detrimental roles in vivo.
• Pro-inflammatory role of DAMPs cannot solely be attributed to their release via RCD.
• Interpretation of the impact of RCD on immunity is extremely challenging.

Immune cell death is often observed in response to infection. There are three potential beneficial outcomes after host cell death: (1) the removal of an intracellular niche for microbes, (2) direct microbicidal activity of released components and (3) the propagation of an inflammatory response. Recent findings suggest that three forms of non-apoptotic regulated cell death, pyroptosis, necroptosis and NETosis, can impact on immunity to bacterial infection. However, it is challenging to design experiments that unequivocally prove the advantageous effects of regulated cell death on immunity. Recent advances in the genetic manipulation of regulated cell death and danger-associated molecular patterns and ‘alarmins’, such as HMGB1 and the IL-1 family, may hold the key to delineating the consequences of cell death in immunity to infection.