Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca ²⁺ mobilization and the inflammatory activity of dendritic cells

Abstract

Innate immune responses to Gram-negative bacteria depend on the recognition of lipopolysaccharide (LPS) by a receptor complex that includes CD14 and TLR4. In dendritic cells (DCs), CD14 enhances the activation not only of TLR4 but also that of the NFAT family of transcription factors, which suppresses cell survival and promotes the production of inflammatory mediators. NFAT activation requires Ca2+ mobilization. In DCs, Ca2+ mobilization in response to LPS depends on phospholipase C γ2 (PLCγ2), which produces inositol 1,4,5-trisphosphate (IP3). Here, we showed that the IP3 receptor 3 (IP3R3) and ITPKB, a kinase that converts IP3 to inositol 1,3,4,5-tetrakisphosphate (IP4), were both necessary for Ca2+ mobilization and NFAT activation in mouse and human DCs. A pool of IP3R3 was located on the plasma membrane of DCs, where it colocalized with CD14 and ITPKB. Upon LPS binding to CD14, ITPKB was required for Ca2+ mobilization through plasma membrane–localized IP3R3 and for NFAT nuclear translocation. Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that induced by the inhibition of NFAT using nanoparticles that delivered an NFAT-inhibiting peptide specifically to phagocytic cells. Our results suggest that ITPKB may represent a promising target for anti-inflammatory therapies that aim to inhibit specific DC functions.

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

“…The endothelial protective effects of empagliflozin have been described in several in-depth studies. In transverse aortic constriction-induced heart failure, empagliflozin was reported to suppress endothelial apoptosis and maintain capillarization through the Akt/eNOS/nitric oxide pathway, thus increasing heart performance [ 18 , 50 ]. Similarly, empagliflozin was found to inhibit leukocyte-endothelium interactions during diabetes by repressing inflammatory cytokine production [ 51 ].…”

How dendritic cells sense and respond to viral infections

“…In the context of inflammation, the expression of CD14 proved to be of fundamental importance. Studies performed in murine and human DCs have shown that CD14 triggers crucial inflammatory pathways [13][14][15]. So far, the role of DC3s in inflammation remains to be clarified, as both a pro-and anti-inflammatory role has been described for these cells depending on the disease context [11,12].…”

“…To further improve selective DC targeting and activation, novel approaches introduced the use of nanoparticles (NPs) as vehicles to deliver viral Ags [15,273] (Figure 3B). Indeed, these carriers constitute in all respects customizable platforms ready to be functionalized and/or encapsulated with everything needed for a focused targeting and activation of DCs.…”

Immunosuppression Affects Neutrophil Functions: Does Calcineurin-NFAT Signaling Matter?

“…For example, bacterial LPS stimulation of murine DCs induced CD14-dependent extracellular Ca 2+ influx, leading to CN-NFAT activation ( 63 ). Recently, these findings were enriched by a study that showed the importance of inositol triphosphate (IP 3 ) receptor 3 (IP 3 R3) and IP3 kinase B (ITPKB) in LPS-induced NFAT activation in mouse and human DCs ( 64 ), signifying an atypical mechanism of Ca2 + mobilization leading to CN-NFAT activation in these cells.…”

“…Some progress is already being made in this regard with the development of next-generation CNI, such as the VIVIT peptide, which selectively inhibits the calcineurin/NFAT interaction, but does not compromise calcineurin’s phosphatase activity ( 104 ). A recent study showed the potential of this peptide, conjugated to nanoparticles designed to target phagocytic cells, to dampen inflammation in a murine model of arthritis ( 64 ). Not only do such approaches hold direct therapeutic potential, but they may also prove invaluable as tools with which to discriminate the roles of CN-NFAT activation in specific cell types, including neutrophils.…”