Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro–IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K+ efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2–deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.

Prolonged sun exposure disrupts the skin’s structural, mechanical, and functional properties, accelerating aging and contributing to skin disorders. To counteract these effects, we developed a formulation containing potent antioxidant, anti-inflammatory, moisturizing, and reparative ingredients to protect and repair sun-damaged skin. The efficacy of the formulation was evaluated through in vitro, ex vivo, and in vivo studies. Results demonstrated that the formulation reduced oxidative stress and suppressed the production of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as lactate dehydrogenase (LDH) secretion, in a photodamaged skin model, nearly reaching levels observed in undamaged skin. It also restored collagen levels, improving structural integrity. In vivo, no adverse reactions were observed when used for 28 or 56 days. The formulation improved skin hydration by up to 46%, reduced transepidermal water loss by 20%, increased luminosity by 70%, and reduced hyperpigmented spots by 14%. It also enhanced skin firmness and elasticity by 30% and reduced wrinkle volume and density by up to 53% and 19%, respectively. These findings demonstrate that the formulation’s active ingredients effectively target the pathways altered by UV exposure, offering considerable potential for preventing and reversing sun-induced skin damage while improving both the appearance and functionality of the skin.

Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1β production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.