Humans have highly variable innate immune responses to infection and tissue damage. This variability is a key factor in explaining why the same pathogen can be cleared with few or no symptoms by one individual, but can trigger a potentially lethal severe acute inflammatory response syndrome akin to sepsis in another. Mixed Lineage Kinase Domain Like (MLKL) is the essential effector of the inflammatory, lytic form of cell death called 'necroptosis'. Necroptosis has evolved primarily to defend against infection. The cellular signaling pathways that culminate in MLKL activation and necroptosis can be induced directly by viral and bacterial components, or as part of the ensuing immune response to pathogens or injury. Left unchecked, MLKL activation can lead to catastrophic cycles of tissue damage and inflammation in mice and humans.
We have isolated a mouse strain with a single missense mutation, MlklD139V, that confers constitutive killing activity to MLKL. Homozygous MlklD139V mutant mice are histologically normal at birth, but develop lethal postnatal inflammation of the salivary glands and around the thymus and heart by 2-3 days of age. The overtly normal embryonic and fetal development of MlklD139V homozygotes, and the absence of any obvious phenotype in MlklD139V heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL below a threshold. These observations also offer an important insight into the potential disease-modulating roles of a cluster of closely situated human MLKL gene variants (which are carried by an estimated 1 in 10 individuals). Have these human MLKL gene variants achieved such high frequencies by chance due to population bottlenecks, or have they conferred a selective survival advantage to one or more pathogens at some point in human history? What are the consequences of carrying these MLKL gene variants in the present day? We have recently shown that combinations of these variants are found at up to 12-fold the expected frequency in patients that suffer from a pediatric auto-inflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO), and are actively investigating the contribution of both common and rare MLKL gene variants to human disease and host defense.