Calcium channel β3 subunit regulates ATP-dependent migration of dendritic cells

Abstract

Migratory dendritic cells (migDCs) continuously patrol tissues and are activated by injury and inflammation. Extracellular adenosine triphosphate (ATP) is released by damaged cells or actively secreted during inflammation and increases migDC motility. However, the underlying molecular mechanisms by which ATP accelerates migDC migration is not understood. Here, we show that migDCs can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated calcium channel subunit β3 (Cavβ3; CACNB3), which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. By contrast, CACNB3 does not regulate lipopolysaccharide-dependent migration. Mechanistically, CACNB3 regulates ATP-dependent inositol 1,4,5-trisphophate receptor–controlled calcium release from the endoplasmic reticulum. This, in turn, is required for ATP-mediated suppression of adhesion molecules, their detachment, and initiation of migDC migration. Thus, Cacnb3 -deficient migDCs have an impaired migration after ATP exposure. In summary, we identified CACNB3 as a master regulator of ATP-dependent migDC migration that controls tissue-specific immunological responses during injury and inflammation.

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma

“…C1 clustered farther apart from all other DCs and expresses signature genes representing plasmacytoid dendritic cells (pDC), such as Siglec-h, Ly6c2, Bst2, Ptprcap, and Tcf4 (Figure 5D, Supplementary Figure 8) (44,45). C3 resembles migratory DCs with high expression of Ccl5, Ccr7, Ccl22, and Cacnb3 (46)(47)(48). None of these populations have significant changes in size based on treatment group (Supplementary Figure 7B).…”

Cavβ3 Contributes to the Maintenance of the Blood-Brain Barrier and Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis

“…The IP3 production assay was performed as described previously. 47 In brief, BMECs were seeded onto a collagen-coated white opaque 384-well microplate at a density of 2×10 4 cells per well and cultured until they achieved confluency. Thereafter, medium was changed, and cells were stimulated with 10 or 60 U/mL thrombin in the presence or absence of YM-254890 (100 nmol/L) or U-73122 (10 µmol/L) for 30 minutes at 37 °C in 5% CO 2 .…”