Key Points Resolving, but not hyperinflammatory stimuli create a microenvironment conducive for the optimal development of adaptive immunity. After onset and resolution, we introduce a third phase to acute inflammatory responses dominated by macrophages and lymphocytes.

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SummaryAcute inflammation is characterized by granulocyte infiltration followed by efferocytosing mononuclear phagocytes, which pave the way for inflammatory resolution. Until now, it was believed that resolution then leads back to homeostasis, the physiological state tissues experience before inflammation occurred. However, we discovered that resolution triggered a prolonged phase of immune suppression mediated by prostanoids. Specifically, once inflammation was switched off, natural killer cells, secreting interferon γ (IFNγ), infiltrated the post-inflamed site. IFNγ upregulated microsomal prostaglandin E synthase-1 (mPGES-1) alongside cyclo-oxygenase (COX-1) within macrophage populations, resulting in sustained prostaglandin (PG)E2 biosynthesis. Whereas PGE2 suppressed local innate immunity to bacterial infection, it also inhibited lymphocyte function and generated myeloid-derived suppressor cells, the net effect of which was impaired uptake/presentation of exogenous antigens. Therefore, we have defined a sequence of post-resolution events that dampens the propensity to develop autoimmune responses to endogenous antigens at the cost of local tissue infection.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli–triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

BackgroundLong-term kidney allograft survival has remained unchanged in recent years despite immunosuppressive and surgical advances. Ischaemia–reperfusion (IR) injury sustained at transplantation contributes to kidney damage that limits allograft lifespan. Interventions to reduce IR injury may prolong graft life, delaying the need for a return to dialysis. Remote ischaemic preconditioning (RIPC), in which brief episodes of non-lethal ischaemia applied to the limb activate a systemic protective reflex against subsequent damaging IR injury, has been reported to cause cardiac, renal and neurological protection in small-scale trials.ObjectivesThe REmote preconditioning for Protection Against Ischaemia–Reperfusion in renal transplantation (REPAIR) trial investigated whether RIPC improves kidney function and other outcomes following living-donor renal transplantation.DesignMulticentre, multinational, double-blind, 2 × 2 factorial designed randomised controlled trial.SettingThirteen tertiary care hospitals in the UK, the Netherlands, Belgium and France.ParticipantsThe REPAIR trial recruited 406 live donor–recipient pairs aged ≥ 18 years. Patients on adenosine triphosphate (ATP)-sensitive potassium channel opening or blocking drugs, on ciclosporin, with a known iodine sensitivity or with ABO incompatibility or those requiring human leucocyte antigen (HLA) antibody removal therapy were excluded.InterventionsEach pair was randomised using a factorial design to one of four groups: sham RIPC, early RIPC (immediately before surgery), late RIPC (24 hours before surgery) and dual RIPC (early and late RIPC). The donor and recipient received the same intervention (active RIPC or sham RIPC) at the two time points.Main outcome measuresThe primary outcome was glomerular filtration rate (GFR) 12 months after transplantation measured by iohexol clearance. Important secondary outcomes were estimated GFR (eGFR) (using routine clinical assessment), safety, inflammatory cytokine profile and biological mechanisms.ResultsIn total, 406 donor–recipient pairs were randomised: 99 to sham RIPC, 102 to early RIPC, 103 to late RIPC and 102 to dual RIPC. Early RIPC resulted in a small but clinically important increase in iohexol GFR (ml/minute/1.73 m2) at 12 months, although the evidence is weak [58.3 vs. 55.9; adjusted difference 3.08, 95% confidence interval (CI) –0.89 to 7.04;p = 0.13], likely because of the higher than expected variability in the iohexol measurements. There was stronger evidence for a treatment effect when eGFR was used and missing values imputed (adjusted difference 3.41, 95% CI –0.21 to 7.04;p = 0.065) and when eGFR was used to assess kidney function (adjusted difference 4.98, 95% CI 1.13 to 8.29;p = 0.011). Late RIPC had no effect on renal outcomes, there was no benefit of combining early and late RIPC and RIPC had no effect on the inflammatory response to surgery. RIPC was safe and well tolerated by recipients and donors.ConclusionsRIPC is a safe intervention in living-donor transplantation. The evidence for an effect of RIPC on GFR (primary outcome) was weak, but other measures of GFR (in our secondary analysis) provided persuasive evidence of a clinically meaningful improvement in kidney function after transplantation. Future work should investigate the role of RIPC in deceased-donor kidney transplantation.Trial registrationCurrent Controlled Trials ISRCTN30083294.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.