Journal
FEBS JOURNAL
Volume 283, Issue 14, Pages 2599-2615Publisher
WILEY-BLACKWELL
DOI: 10.1111/febs.13775
Keywords
apoptosis; cell death; damage-associated molecular patterns; IL-1 family; inflammation; injury; necrosis; sterile injury; wound healing
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Funding
- Science Foundation Ireland [14/IA/2622]
- Science Foundation Ireland (SFI) [14/IA/2622] Funding Source: Science Foundation Ireland (SFI)
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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 (DAMPs), 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 DAMPs, little consensus has emerged concerning which of these represent the key activators of sterile inflammation. Here I argue that the canonical DAMPs have long been hiding in plain sight, in the form of members of the extended IL-1 cytokine family (IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, and IL-36 gamma). The latter cytokines possess all of the characteristics expected of endogenous DAMPs and initiate inflammation in a manner strikingly similar to that utilized by the other major category of inflammatory triggers, pathogen-associated molecular patterns (PAMPs). Furthermore, many PAMPs upregulate the expression of IL-1 family DAMPs, enabling robust synergy between these distinct classes of inflammatory triggers. Thus, multiple lines of evidence now suggest that IL-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.
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