In 1989, Janeway (1) introduced a conceptual framework to understand how the innate immune system selectively responds to potentially threatening infections. Based on empirical observations, he proposed that the innate immune system must not only distinguish foreign cells from native cells, but also requires the presence of pathogenic costimulatory molecules to initiate inflammatory signaling cascades (1, 2). These signals, typified by gram-negative LPS and termed “pathogen-associated molecular patterns”(PAMPs), are molecularly distinct, foreign particles that serve as necessary immune adjuvants, causing local inflammation and tissue destruction (3). This theory was corroborated by the discovery of a new class of receptors known as PRRs (pattern-recognition receptors)(4, 5). This broad class of receptors, typified by the TLR (Toll-like receptor) family, bind structurally conserved moieties, such as microbial cell wall fragments and foreign DNA (Figure 1)(6). The activation of these receptors is responsible for local inflammation, most distinctly through the induction of multiple pathways, including the TNF (tumor necrosis factor)-a/NF-kB (nuclear factor-kB) signaling cascade as well as NLRP3 (nucleotidebinding oligomerization domain, leucine rich repeat and pyrin domain containing 3) inflammasome activation with production of inflammatory molecules, such as IL-1b and IL-18 (Figure 2). PRR activation also recruits and activates circulating leukocytes, such as macrophages and neutrophils, which enhance microbial killing through the release of reactive oxygen species, proteases, and IFNg (7).

This framework, however, fails to explain the systemic inflammatory response observed during noninfectious critical illness, such as major trauma, burns, or cardiac arrest; nor does it explain the prolonged organ dysfunction in sepsis despite clearance of the original infection. In 1994, a complimentary model was proposed, coined the “danger” model (8). Based purely on theoretical grounds, the “danger” model hypothesized that unregulated, necrotic cell death must release endogenous molecules that trigger the innate immune system, leading to local “sterile” inflammation and tissue destruction. Definitive empirical evidence for this concept developed throughout the 1990s by observation of local cellular reaction to necrotic and apoptotic cell death. Several molecules were discovered in this period that can bind to PRRs and initiate local inflammatory responses (9–12). These activators of the innate immune system have been named alarmins, cell