Resolution of Inflammation: What Controls Its Onset?

Abstract

An effective resolution program may be able to prevent the progression from non-resolving acute inflammation to persistent chronic inflammation. It has now become evident that coordinated resolution programs initiate shortly after inflammatory responses begin. In this context, several mechanisms provide the fine-tuning of inflammation and create a favorable environment for the resolution phase to take place and for homeostasis to return. In this review, we focus on the events required for an effective transition from the proinflammatory phase to the onset and establishment of resolution. We suggest that several mediators that promote the inflammatory phase of inflammation can simultaneously initiate a program for active resolution. Indeed, several events enact a decrease in the local chemokine concentration, a reduction which is essential to inhibit further infiltration of neutrophils into the tissue. Interestingly, although neutrophils are cells that characteristically participate in the active phase of inflammation, they also contribute to the onset of resolution. Further understanding of the molecular mechanisms that initiate resolution may be instrumental to develop pro-resolution strategies to treat complex chronic inflammatory diseases, in humans. The efforts to develop strategies based on resolution of inflammation have shaped a new area of pharmacology referred to as "resolution pharmacology."

Keywords: chemokine depletion; eicosanoids; pro-resolving mediators; resolution; tissue homeostasis.

Figure 1

Overview of cellular and molecular processes that govern inflammation and its resolution. During early phase of inflammation, production of inflammatory mediators promotes leukocyte accumulation and survival in the inflammatory site. While the inflammatory response evolves, several mechanisms enable the fine-tuning of these phenomena creating a favorable environment for the resolution phase leading to return to tissue homeostasis. Chemokine proteolysis, sequestration by atypical receptors, and degradation by neutrophil extracellular traps (NETs) are important mechanisms to shape chemokine gradients restricting the influx of neutrophils, once sufficient numbers of cells have been recruited. In addition, inflammatory mediators may induce a negative-feedback loop downregulating the production of inflammatory cytokines. Prostaglandins generated in the active phase of inflammation are involved in the switch from proinflammatory lipid production to the synthesis of lipoxins and other pro-resolving lipids, within inflammatory exudates. Mediators released early in inflammation, like ACTH, can also enable the induction of the pro-resolving phase. Upon activation, neutrophils release microparticles containing pro-resolution mediators that control further granulocyte ingress and turn on a resolution and tissue reparative programs. AnxA1 is a major component of the pro-resolving properties of neutrophil-derived microvesicles. Many resolution mediators downregulate survival pathways and activate apoptosis of granulocytes. Apoptotic neutrophils release pro-resolving mediators that contribute to inhibition of continued neutrophil infiltration and to recruitment of monocytes in a non-phlogistic manner. Upon apoptosis, neutrophils also promote their own clearance by expressing find me and eat me signals that attract scavengers and allow the identification of the dying cell, respectively. In response to local mediators and upon efferocytosis, proinflammatory macrophages switch to resolution-phase macrophages. These events will reestablish tissue homeostasis.