Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons From Asthma and Inflammatory Bowel Disease

Abstract

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.

Keywords: asthma; chronic inflammatory bowel disease; eicosanoids; immune fitness; inflammation; resolution.

Figure 1

Dynamics of the inflammatory response in chronic inflammation. The acute inflammatory response is a highly coordinated sequence of events characterized by an onset phase coordinated by several families of chemokines, cytokines, and pro-inflammatory mediators that is followed in health by an active resolution phase brought about by the engagement of specific cellular mechanisms under the control of several pro-resolving mediators to promote resolution of the tissue inflammation as well as healing and repair. A failure in pro-resolving pathways can extend in time the actions of pro-inflammatory mechanisms resulting in prolonged or chronic inflammation with recurrent exacerbations.

Figure 2

Key cellular actors of resolution. For effective resolution of inflamed tissues to occur and to restore tissue homeostasis, specific cellular mechanisms that are under the control of pro-resolving mediators are enlisted. They promote termination of the inflammatory response and initiate tissue repair and healing. Pro-inflammatory mediators: red circles, pro-resolving mediators: blue circles. Anx, annexin; DCs, Dendritic cells; Eos, eosinophils; Gal, Galectin; IBD, inflammatory bowel disease; IL, interleukin; ILC2, Type 2 innate lymphoid cells; ILC3, Type 3 innate lymphoid cells; MDSCs, Myeloid-derived suppressor cells; MiRs, MicroRNAs; NK, Natural killer; PMN, polymorphonuclear cells; TGF-beta, Transforming growth factor beta; Th1, Type 1 T helper cells; Th2, Type 2 T helper cells; Treg, regulatory T cells; SPMs, specialized pro-resolution lipid mediators; VIP, vasoactive intestinal peptide.

Figure 3

Overview of the pathways for synthesis of resolvins from omega-3 polyunsaturated fatty acids, DHA and EPA. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid, MaR, maresin; PD, protectin; Rv, resolvin.

Figure 4

Specialized pro-resolving lipid mediators signal through G-protein coupled receptors on a variety of cell involved (deranged) immune response leading to cell specific responses. Akt, protein kinase B; ALX/FPR2, N-formyl peptide receptor 2—LXA₄ receptor; AnxA1, annexin A1; BLT1, leukotriene B₄ receptor 1; CD, cluster domain; CMKLR1, chemokine like receptor 1 or Chemerin Receptor 23; DVR1, RvD1 receptor or G protein coupled receptor (GRP)32; DVR2, RvD2 receptor or GRP18; ERK, extracellular signal regulated kinases; IL, interleukin; INFγ, interferon γ; Mcl-1, anti-apoptotic protein in mast cells; miR, microRNA; mTOR, mammalian target of rapamycin; NK cell, natural killer cell; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, phosphorylated; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; PMN, polymorphonuclear cells; Rv, resolvin; LX, lipoxin; S6K, ribosomal protein S6 kinase; Th17 cell: Thelper 17 lympocyte; Treg cell: regulatory T lymphocyte; TNFα, tumor necrosis factor α; Traf6: TNF receptor associated factor 6.

Figure 5

New resolution-based strategies able to direct the inflammatory processes in a controlled way.