HDAC6 Mediates Poly (I:C)-Induced TBK1 and Akt Phosphorylation in Macrophages

Abstract

Macrophages are derived from monocytes in the bone marrow and play an important role in anti-viral innate immune responses. Macrophages produce cytokines such as interferons and IL-10 upon viral infection to modulate anti-viral immune responses. Type I interferons (IFNs) promote anti-viral defense. IL-10 is a suppressor cytokine that down-regulates anti-viral immune responses. HDAC6 is a tubulin deacetylase that can modulate microtubule dynamics and microtubule-mediated cell signaling pathways. In the present study, we investigated the potential role of HDAC6 in macrophage anti-viral responses by examining poly (I:C)-induced IFN-β and IL-10 production in mouse bone marrow-derived macrophages (BMDMs). We also investigated the role of HDAC6 in poly (I:C)-induced anti-viral signaling such as TBK1, GSK-3β, and Akt activation in mouse BMDMs. Our data showed that HDAC6 deletion enhanced poly (I:C)-induced INF-β expression in macrophages by up-regulating TBK1 activity and eliminating the inhibitory regulation of GSK-3β. Furthermore, HDAC6 deletion inhibited poly (I:C)-induced suppressor cytokine IL-10 production in the BMDMs, which was associated with the inhibition of Akt activation. Our results suggest that HDAC6 modulates IFN-β and IL-10 production in macrophages through its regulation of TBK1, GSK-3β, and Akt signaling. HDAC6 could act as a suppressor of anti-viral innate immune responses in macrophages.

Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients

“…Histone deacetylase 6 (HDAC6) is a special histone deacetylase with two deacetylation domains and one ubiquitination domain. HDAC6 plays a center role in several processes, including positive regulation of peptidyl-serine phosphorylation, protein deacetylation, protein destabilization, microtubule stability (Olzmann et al, 2007;Wang et al, 2018;Wang et al, 2020a;Osseni et al, 2020;Wang et al, 2022). Our study showed that histone deacetylase HDAC6 was expressed heterogeneously in different primordial follicles.…”

Histone deacetylase 6’s function in viral infection, innate immunity, and disease: latest advances

“…Recent research on HDAC6 activity emphasizes its importance in the innate immune response to viral infection. Studies on HDAC6’s function in the infection of viruses have mostly focused on three aspects: (a) controlling viral transport, fusion, and viral component release by modulating plasma membrane dynamics and the cytoskeleton ( 55 , 56 , 62 , 63 , 74 , 77 ); (b) influencing host cells’ antiviral immune response ( 19 , 23 , 69 ); (c) tuning the breakdown of viral or host proteins in host cells through autophagy ( 64 , 68 , 78 ).…”

“…TANK-binding kinase 1 (TBK1), an IKK-related serine/threonine kinase, plays a big role in antiviral immunity ( 98 – 101 ). Recent research shows that HDAC6 controls the phosphorylation of TBK1 and Akt in macrophages by poly (I:C) ( 23 ). Reports show that when double-stranded RNA (dsRNA) binds to TLR3, it turns on TBK1 and starts signaling transduction that leads to the production of IFN-I ( 98 – 101 ).…”

“…Numerous studies indicate that MTs and GSK-3β have intimate interactions ( 107 – 109 ). Poly (I:C) induced IFN-β expression in macrophages was elevated after HDAC6 deletion, which influenced IFN-I and IL-10 production via enhancing TBK1 activity and removing GSK-3β inhibitory regulation ( 23 ). The results of the experiments with HDAC6 knockout mice highlight the effect of HDAC6 deletion on the immune system, confirming the importance of HDAC6 in viral infection.…”

“…HDAC6 depletion or inhibition promotes virus accumulation in cells, indicating a reduced ability for virus intracellular neutralization mediated by antibodies ( 22 ), which confirmed that HDAC6 is a new activator of TRIM21-mediated anti-viral innate immune response. Furthermore, HDAC6 deletion suppressed poly (I:C)-induced Akt activation, as evidenced by decreased phosphorylation of Akt at Ser473 near the carboxy terminus, implies that HDAC6 might control the degree to which macrophages activate Akt during viral infection ( 23 ). The findings imply that HDAC6 may modulate macrophage innate immunological responses to viruses.…”