Phosphodiesterase 10A Is a Key Mediator of Lung Inflammation

Abstract

Cyclic nucleotides cAMP and cGMP are important regulators of immune cell functions. Phosphodiesterases (PDEs) hydrolyze cAMP and/or cGMP and, thus, play crucial roles in cyclic nucleotide homeostasis. Abnormal alterations of PDE expression have been implicated in several diseases. To understand the function of PDEs in macrophages, we screened for all PDE genes in both peritoneal and alveolar macrophages from C57BL/6J mice and found that PDE4B and PDE10A are highly induced by LPS. A number of PDE4 inhibitors have been used clinically for the treatment of inflammatory lung diseases. However, the role of PDE10A in inflammation is still poorly understood. We therefore investigated the role of PDE10A in macrophage inflammatory response in vitro and acute lung inflammation in vivo. We found that LPS induces a sustained PDE10A expression in macrophages, which is different from a transient induction by PDE4B. PDE10A inhibition blocked LPS-induced MCP-1 expression, but not TNF-α, whereas PDE4B inhibition blocked LPS-induced TNF-α expression, but not MCP-1. In addition, PDE10A inhibition or deficiency decreased LPS-induced HIF-1α protein expression and subsequently suppressed MCP-1 expression. In vivo, PDE10A expression was also elevated in lung tissue after LPS exposure. Global PDE10A knockout or systemic administration of the PDE10A inhibitor TP-10 in mice significantly suppressed inflammatory molecule levels in the lung tissue and bronchoalveolar lavage fluid as well as inflammatory cell infiltration. These findings show that PDE10A plays a critical role in lung inflammation by promoting the activation of resident macrophages and infiltration of neutrophils.

The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis

“…To test the ability of exogenous HNE to inhibit lung injury and inflammasome activation in vivo, we used the LPS induced ALI model (49)(50)(51). C57BL/6 mice were exposed to a single dose of saline, HNE, LPS or LPS+HNE by oropharyngeal delivery.…”

“…Peritoneal macrophage isolation was performed as previously described (51,82). One ml of sterile Bio-Gel P-100 polyacrylamide beads (Bio-Rad, 150-4174) in PBS (2% w/v) was injected IP into male and female C57BL/6J.…”

Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages

“…Peritoneal macrophage isolation: Peritoneal macrophages were stimulated by injecting mice intraperitoneally with 1 mL of sterile 2% Bio-Gel® P Polyacrylamide Beads (Bio-Rad, 150-4174, Hercules, CA), and were subsequently harvested 4 days later by flushing the peritoneal cavity with 5 ml ice-cold phosphate-buffered saline (PBS) and plated in 6-well plates (5 × 10 5 cells/well) in RPMI medium 1640 (Thermo Fisher Scientific, 11875-093, Waltham, MA) supplemented with 10% fetal bovine serum (Gibco, 10437-028, Waltham, MA), 100 U/mL penicillin, and 100 μg/mL streptomycin, 1% pyruvate (Thermo Fisher Scientific, 11360070). The next day, cells were washed with serum-free medium twice before use (48). Bone marrow progenitor cell isolation and bone marrow-derived macrophage (BMDM) differentiation: BMDMs preparation was performed as previously described (49).…”

Nitric Oxide and Cancer: When to Give and When to Take Away?

“…With respect to cancer progression and therapy, cGMP is a key mediator of angiogenesis and neovascularization and also provides an alternative mechanism in the inhibition of immune cell infiltration into inflamed tissue. 18 The second level (∼100−500 nM) is referred to as nitrosative signaling because it involves nitrosative modifications of proteins. This NOS2-driven concentration zone involves two major target types through direct but kinetically slow interactions with nonheme iron 19−21 and nitrosation of critical membrane thiols.…”

“…The lowest level of NO (<100 nM) primarily involves direct effects, particularly through nitrosylation of the heme group in soluble guanylyl cyclase (sGC). , Subsequent production of cyclic guanosine 3′,5′-monophosphate (cGMP) is involved in the regulation of numerous biological processes. With respect to cancer progression and therapy, cGMP is a key mediator of angiogenesis and neovascularization and also provides an alternative mechanism in the inhibition of immune cell infiltration into inflamed tissue …”