Inflammation is a major cause of morbidity, as illustrated by debilitating conditions such as rheumatoid arthritis and inflammatory bowel diseases. IL-1β and TNF are key mediators of inflammation, and agents that neutralize their effects have provided relief for millions of patients, but we may have yet more to discover about inflammation.
In this issue, Kim et al. show that mice with a hypomorphic mutation of Wdr1 (i.e., a mutation that results in underproduction of an otherwise normal product) develop inflammation caused by IL-18.
This is interesting for several reasons. To the cell biologist, Wdr1 is a protein that interacts with filamentous actin. It is the murine homologue of human actin-interacting protein 1 (AIP1). The dynamics of cellular actin is crucial in cell biology and underlies fundamental cellular functions such as cell division, movement, and phagocytosis. Actin oscillates between filamentous actin and soluble actin. Cofilin binds filamentous actin and severs the filaments, causing these to dissemble, yielding soluble actin. Wdr1 in mice and AIP1 in humans bind the cofilin/filamentous actin complex and energize cofilin’s ability to sever the filaments. Null mutations of Wdr1 are embryonic lethal; mice with hypomorphic mutations of Wdr1 are viable but have thrombocytopenia and their neutrophils have crawling defects. These mice also develop autoinflammation.
The inflammasome is to immunologists what actin is to cell biologists. Intracellular sensors, such as the NOD-like receptors (NLRs) and the absent in melanoma 2 (AIM2)–like receptors (ALRs), sense damage or danger signals and recruit ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain). In this complex, ASC generates caspase-1 by proteolytic cleavage of procaspase-1. Caspase-1 in turn cleaves pro–IL-1β and pro–IL-18, generating the potent proinflammatory cytokines IL-1β and IL-18 that are secreted from the cell.
Kim et al. report on a significant amount of work involving a comprehensive analysis of this novel mouse model. They show that myeloid cells from hypomorphic Wdr1 mutants have more filamentous actin than wild-type mice with spontaneous activation of ASC and caspase-1; the cells generate huge amounts of IL-1β and IL-18 as expected. This points to a critical role for actin dynamics in controlling the inflammasome. Surprisingly, the mice suffer inflammation of cartilage tissue rather than a generalized inflammation, and the inflammation is caused not by the elevated IL-1β but by IL-18. Furthermore, monocytes and not macrophages, neutrophils, or dendritic cells are responsible for the production of IL-18. The authors observed massive infiltration of neutrophils, but it was monocytes that migrated to the tissue, produced IL-18 locally, and initiated the inflammation.
This study provides a cellular framework for understanding the role of IL-18 in inflammation. This is a novel and intriguing paper that implicates the actin-depolymerizing cofactor Wdr1 in the regulation of the pyrin inflammasome and IL-18 production by monocytes. These results add to the growing literature on the role of actin polymerization in inflammation and may have translational implications for the therapy of patients with autoinflammatory conditions.