Cell death and inflammation: the case for <scp>IL</scp>‐1 family cytokines as the canonical <scp>DAMP</scp>s of the immune system

<jats:p>It is well known that necrotic cells are capable of promoting inflammation through releasing so‐called endogenous ‘danger signals’ that can promote activation of macrophages, dendritic cells, and other sentinel cells of the innate immune system. However, the identity of these endogenous proinflammatory molecules, also called damage‐associated molecular patterns (<jats:styled-content style="fixed-case">DAMP</jats:styled-content>s), has been debated since the ‘danger model’ was first advanced 20 years ago. While a relatively large number of molecules have been proposed to act as <jats:styled-content style="fixed-case">DAMP</jats:styled-content>s, little consensus has emerged concerning which of these represent the key activators of sterile inflammation. Here I argue that the canonical <jats:styled-content style="fixed-case">DAMP</jats:styled-content>s have long been hiding in plain sight, in the form of members of the extended <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1 cytokine family (<jats:styled-content style="fixed-case">IL</jats:styled-content>‐1α, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1β, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐18, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐33, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐36α, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐36β, and <jats:styled-content style="fixed-case">IL</jats:styled-content>‐36γ). The latter cytokines possess all of the characteristics expected of endogenous <jats:styled-content style="fixed-case">DAMP</jats:styled-content>s and initiate inflammation in a manner strikingly similar to that utilized by the other major category of inflammatory triggers, pathogen‐associated molecular patterns (<jats:styled-content style="fixed-case">PAMP</jats:styled-content>s). Furthermore, many <jats:styled-content style="fixed-case">PAMP</jats:styled-content>s upregulate the expression of <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1 family <jats:styled-content style="fixed-case">DAMP</jats:styled-content>s, enabling robust synergy between these distinct classes of inflammatory triggers. Thus, multiple lines of evidence now suggest that <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1 family cytokines represent the key initiators of necrosis‐initiated sterile inflammation, as well as amplifiers of inflammation in response to infection‐associated tissue injury.</jats:p>