Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1.

The respiratory epithelium consists of lung sentinel cells, which are the first to contact inhaled inflammatory insults, including air pollutants, smoke, and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation resolution is now known to be an active process involving a new genus of lipid mediators, called "specialized proresolving lipid mediators," that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts proinflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. In this article, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic polyinosinic-polycytidylic acid [poly(I:C)] in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and proinflammatory signaling involving MAPKs and NF-κB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1 (TGF-ß-activated kinase 1), a key upstream regulatory kinase common to both the MAPK and NF-κB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 (TAK1 binding protein), and TRAF6 (TNF receptor-associated factor 6). We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on human small airway epithelial cells. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. In this article, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and proresolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses.

A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation.

INTRODUCTION: Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation. METHODS: Primary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1ß or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed. RESULTS: RvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure. CONCLUSIONS: RvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.