Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.

Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients' quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)-mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs.

Gasdermins: New Therapeutic Targets in Host Defense, Inflammatory Diseases, and Cancer.

Gasdermins (GSDMs) are a class of pore-forming proteins related to pyroptosis, a programmed cell death pathway that is induced by a range of inflammatory stimuli. Small-scale GSDM activation and pore formation allow the passive release of cytokines, such as IL-1β and IL-18, and alarmins, but, whenever numerous GSDM pores are assembled, osmotic lysis and cell death occur. Such GSDM-mediated pyroptosis promotes pathogen clearance and can help restore homeostasis, but recent studies have revealed that dysregulated pyroptosis is at the root of many inflammation-mediated disease conditions.

Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency.

Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti-tumor necrosis factor therapy reduces strokes and systemic inflammation.

Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes.

The inflammasome is an intracellular multi-protein complex that orchestrates the release of the pro-inflammatory cytokines IL-1β and IL-18, and a form of cell death known as pyroptosis. Tyrosine phosphorylation of the inflammasome sensors NLRP3, AIM2, NLRC4, and the adaptor protein, apoptosis-associated speck-like protein (ASC) has previously been demonstrated to be essential in the regulation of the inflammasome. By using the pharmacological protein tyrosine phosphatase (PTPase) inhibitor, phenylarsine oxide (PAO), we have demonstrated that tyrosine dephosphorylation is an essential step for the activation of the NLRP3 and AIM2 inflammasomes in human and murine macrophages.