Innate immune sensing of macromolecule homeostasis

The innate immune system uses a distinct set of germline-encoded pattern recognition receptors to recognize molecular patterns initially thought to be unique to microbial invaders, named pathogen-associated molecular patterns. The concept was later further developed to include similar molecular patterns originating from host cells during tissue damage, known as damage-associated molecular patterns. However, recent advances in the mechanism of monogenic inflammatory diseases have highlighted a much more expansive repertoire of cellular functions that are monitored by innate immunity. Here, we summarize several examples in which an innate immune response is triggered when homeostasis of macromolecule in the cell is disrupted in non-infectious or sterile settings. These ever-growing sensing mechanisms expand the repertoire of innate immune recognition, positioning it not only as a key player in host defense but also as a gatekeeper of cellular homeostasis. Therapeutics inspired by these advances to restore cellular homeostasis and correct the immune system could have far-reaching implications.