Orai2 channel regulates prostaglandin E2 production in TNFα/IL1α-stimulated astrocytes.

Abstract

Astrocytes are glial cells that serve homeostatic functions in the central nervous system (CNS). Recent research, however, suggests that under pathological conditions, astrocytes are stimulated by various factors and actively participate in CNS inflammation. In the present study, we found that astrocytes upregulate various inflammatory factors including prostaglandin E2 (PGE2 ) by co-stimulation with tumor necrosis factor-alpha (TNFα) and interleukin-1alpha (IL1α). These TNFα/IL1α-stimulated astrocytes also showed increased Ca2+ release from the endoplasmic reticulum (ER) and increased expression of Orai2, a member of the store-operated calcium channel (SOCC) family. To reveal the role of Orai2, we used astrocytes in which Orai2 was knocked-down (KD) or knocked-out (KO). The expression of the prostaglandin E synthase Ptges and the production of PGE2 were higher in Orai2-KD astrocytes than in WT astrocytes when stimulated with TNFα and IL1α. Orai2-KO astrocytes also showed increased expression of Ptges and increased PGE2 production. The expression of Ptgs2, another PGE2 synthetic enzyme, was also upregulated in Orai2-KO astrocytes. Moreover, Orai2-KO astrocytes showed increased store-operated calcium entry (SOCE) and increased Orai1 expression. These results suggest that Orai2 is upregulated in TNFα/IL1α-stimulated astrocytes and reduces PGE2 production to some extent, modulating CNS inflammation. Our findings may aid in understanding how astrocytes are associated with inflammatory responses, and the identification of new targets that modulate astrocytic reactivity.

• Authors: Hiroki Nakajima, Sayaka Fujita, Masashi Kakae, Kazuki Nagayasu, Masatsugu Oh-Hora, Hisashi Shirakawa, Shuji Kaneko
• Journal: Glia (Glia) Vol. 70 Issue 9 Pg. 1666-1680 (09 2022) ISSN: 1098-1136 [Electronic] United States
• PMID: 35506586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Interleukin-1alpha
• ORAI2 Protein
• Orai2 protein, mouse
• Prostaglandins E
• Tumor Necrosis Factor-alpha
• Calcium

Topics

• Animals
• Astrocytes (metabolism)
• Calcium (metabolism)
• Calcium Signaling
• Inflammation
• Interleukin-1alpha (metabolism, pharmacology)
• Mice
• ORAI2 Protein (metabolism)
• Prostaglandins E (metabolism)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)