Switching off key signaling survival molecules to switch on the resolution of inflammation

Abstract

Inflammation is a physiological response of the immune system to injury or infection but may become chronic. In general, inflammation is self-limiting and resolves by activating a termination program named resolution of inflammation. It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases. Resolution of inflammation is an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signaling molecules associated with cytokine production and leukocyte survival. Apoptosis of leukocytes (especially granulocytes) is a key element in the resolution of inflammation and several signaling molecules are thought to be involved in this process. Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.

Figure 1

Targets to promote granulocyte apoptosis and inflammation resolution. During early phase of inflammation production of proinflammatory mediators and activation of signal survival pathways (PI3K/Akt, NF-κB, MAPKs, and CDKs) promotes leukocyte accumulation and survival in the inflammatory site. While inflammatory response evolves, local activation/release of proresolution mediators occurs and pathways (H₂O₂, AnxA1, and cAMP) that control further granulocyte ingress and turn on a resolution program. These resolution molecules, in addition to proresolving lipid mediators which are not highlighted in this cartoon, downregulate survival pathways and activate an apoptosis-associated program in granulocytes. Resolution molecules are also able to promote efferocytosis and coordinate reprogramming of macrophages. These events will reestablish tissue homeostasis.