TNF-αは静脈内皮細胞におけるClaudin-11低下を介して静脈からのChloride漏出を誘導する

この論文で著者らはTNF-αが静脈特異的にChlorideイオンの漏出を促進し、その過程にはTNF-αによる静脈内皮細胞の細胞間tight junctionタンパクClaudin-11の低下が関与していることを明らかにしました。TNF-αの下流ではPanx1 channel活性化→TRPV4 Ca++ channelの活性化が生じ、これがATPの細胞外への放出を誘導します。放出されたATPはendonucleotidease CD39によってadenosineへと加水分解を受け、A2A adenosine受容体の活性化を誘導し、結果として静脈内皮細胞におけるClaudin-11の低下と漏出増加をきたします。著者らはこれが敗血症におけるTNF-αの病態形成メカニズムの一つではないかとしています。

関節リウマチの病態においてもTNF-αによる静脈からのChloride漏出が関与しているのでしょうか？ところでMTXは細胞外adenosineを増加させ、A2A 受容体を活性化することが抗炎症作用に働く可能性が報告されています。A2A 受容体活性化という点ではMTXとTNF-αと共通しているようにも思えるのですが、両者の作用がどのような関係にあるのかは興味深いところです。

Maier-Begandt D et al., A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability. Sci Signal. 2021 Mar 2; 14(672): eaba2940.

A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability

A challenge in treating sepsis, a potentially life-threatening, systemic inflammatory disorder, is the increase in endothelial permeability that leads to widespread tissue edema and immune cell infiltration. Maier-Begandt et al. uncovered a signaling pathway activated specifically in veins by TNFα, a proinflammatory cytokine whose circulating concentrations increase greatly during sepsis. TNFα treatment resulted in the activation of Panx1 channels, which stimulated a signaling pathway that led to disrupted tight junctions in veins but not in arteries. Sepsis induced less lung edema and was less fatal to Panx1-deficient mice compared to control mice. Thus, targeting this pathway may improve survival in patients experiencing sepsis. The endothelial cell barrier regulates the passage of fluid between the bloodstream and underlying tissues, and barrier function impairment exacerbates the severity of inflammatory insults. To understand how inflammation alters vessel permeability, we studied the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNFα specifically decreased the barrier function of venous endothelium without affecting that of arterial endothelium. On the basis of RNA expression profiling and protein analysis, we found that claudin-11 (CLDN11) was the predominant claudin in venous endothelial cells and that there was little, if any, CLDN11 in arterial endothelial cells. Consistent with a difference in claudin composition, TNFα increased the permselectivity of Cl− over Na+ in venous but not arterial endothelium. The vein-specific effects of TNFα also required the activation of Pannexin 1 (Panx1) channels and the CD39-mediated hydrolysis of ATP to adenosine, which subsequently stimulated A2A adenosine receptors. Moreover, the increase in vein permeability required the activation of the Ca2+ channel TRPV4 downstream of Panx1 activation. Panx1-deficient mice resisted the pathologic effects of sepsis induced by cecal ligation and puncture on life span and lung vascular permeability. These data provide a targetable pathway with the potential to promote vein barrier function and prevent the deleterious effects of vascular leak in response to inflammation.

A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability