Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

Abstract

Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation - that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.

Figure 1. Cardinal signs of inflammation and its resolution.

Tissue- and organism-level responses to inflammation have been well recognized for centuries and can be summarized as the 'five pillars of inflammation'; namely, calor (fever), rubor (redness), tumor (swelling and oedema), dolor (pain) and functio laesa (loss of function). With the recognition that the resolution of inflammation is an active process, recent research has identified molecular and cellular processes that promote catabasis. These can be summarized as the 'five pillars of resolution'; that is, removal of microorganisms, dead cells and debris, restoration of vascular integrity and perfusion, tissue regeneration, remission of fever and relief from inflammatory pain. PowerPoint slide

Figure 2. Polyunsaturated fatty acids are substrates for specialized pro-resolving mediators.

Stereoselective mediators that enhance host defence, resolve tissue inflammation and stimulate tissue regeneration have been described4. These specialized pro-resolving mediators (SPMs) are produced in a spatio-temporally regulated manner from essential polyunsaturated fatty acids (PUFAs) that are either released enzymatically by phospholipase A₂ (PLA₂) from cell membranes for secondary conversion by biosynthetic enzymes or delivered with oedema fluid from plasma to exudates. The principal SPM families are lipoxins from arachidonic acid (C20:4n-6; in light blue), as well as the E-series resolvins from eicosapentaenoic acid (C20:5n-3; in pink) and D-series resolvins, protectins and maresins from docosahexaenoic acid (C22:6n-3; in green). The SPM precursors eicosapentaenoic acid and docosahexaenoic acid are essential omega-3 PUFAs. Representative members of these families, their structures and receptors are shown here. CMKLR1, chemokine-like receptor 1; GPR32, probable G protein-coupled receptor 32; LX, lipoxin; MaR1, maresin 1; NPD1, neuroprotectin D1; RvD1, resolvin D1; RvE, resolvin E. PowerPoint slide

Figure 3. Cellular mechanisms for SPMs in lung anti-inflammation and pro-resolution.

During a self-limited inflammatory response, resolution of inflammation is an active process governed by specialized pro-resolving mediators (SPMs) that transmit both anti-inflammatory (red) and pro-resolving (blue) actions to leukocytes and tissue-resident cells. This class of endogenous immunoresolvents induces an anti-inflammatory response by inhibiting granulocyte migration and activation, disrupting sensory neuron activation and dampening cytokine production by a variety of structural cells, including epithelial cells, endothelial cells and fibroblasts. SPMs have a multipronged action to regulate sentinel innate lymphoid cells to decrease cytokine and increase amphiregulin production. These mediators also promote resolution by inducing regulatory T cells to control innate lymphoid cells, stimulating natural killer cells to trigger granulocyte apoptosis and engaging macrophages in a non-phlogistic manner to engulf bacteria and noxious stimuli, and clear apoptotic cells by efferocytosis. IL-5, interleukin-5; O₂⁻, superoxide; TNF, tumour necrosis factor; TRPV1, transient receptor potential cation channel subfamily V member 1. PowerPoint slide

Figure 4. Selected SPMs increase antiviral host defence.

In hosts infected with influenza viruses, endogenous protectin D1 production is increased. Protectin D1 limits influenza pathogenicity by directly interacting with the RNA replication machinery to inhibit viral RNA nuclear export. In particularly virulent strains of influenza, such as the H5N1 avian (A) strain, protectin D1 formation is not sufficiently upregulated, leading to more efficient viral replication and host demise. Treatment of the host with exogenous protectin D1 can restore inhibition of viral RNA export, thereby limiting viral replication and improving host survival. PowerPoint slide