Volume 21 Issue 1, January 2020

NLRP3-driven sterile inflammation facilitates the pathogenesis of various human inflammatory diseases. New work identifies apolipoprotein C3 as an endogenous NLRP3 agonist that promotes sterile inflammation and organ damage.

IL-33 is shown to play a cell-intrinsic role in maintenance of the functional identity of regulatory T cells in the tumor microenvironment. Genetic inhibition of IL-33 potentiates the therapeutic effect of checkpoint inhibitor immunotherapy in a melanoma mouse tumor model.

Hypoxia and acidity in the tumor microenvironment promote resistance to immunotherapy. Hypoxia upregulates multiple immunoinhibitory pathways, including VISTA, and acidity enables VISTA to interact with PSGL-1 to inhibit immune activation selectively in the acidic tumor microenvironment.

Ablasser and Hur review the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs.

Overabundance of apolipoprotein C3 (ApoC3) is associated with atherosclerosis. Speer and colleagues demonstrate that ApoC3 activates the NLRP3 inflammasome via a non-canonical pathway contributing to inflammation and development of atherosclerosis.

Oxidized host-derived phospholipids such as oxPAPC can play important roles in atherosclerosis. Zanoni and colleagues demonstrate that oxPAPC generates a distinctive metabolic and hyperinflammatory profile in macrophages that can drive atherosclerosis in mice.

Croker and colleagues show that the phosphatase Ptpn6 functions to suppress neutrophil cell death pathways and IL-1 release, thereby limiting autoinflammatory responses.

Pasare and colleagues describe an inflammasome-independent, TNFR–Fas–caspase-8-dependent pathway of IL-1β production triggered by cognate interactions between effector CD4⁺ T cells and mononuclear phagocytes.

IL-33, an IL-1 family member, plays dual roles as an intracellular transcription factor and as an extracellular alarmin of tissue damage. Verginis and colleagues identify a cell-intrinsic role for nuclear IL-33 stabilizing T_reg cell suppressor function in tumor environments.

The International Mouse Phenotyping Consortium (IMPC) aims to identify the function of all protein-coding genes in the mouse genome. Hayday and colleagues leverage 530 knockout lines from the IPMC to develop the 3i Project, which immunophenotypes mice and leads to the identification of new and unexpected gene influences on immune function and on the structural organization of the immune system.