PPARγ and the Innate Immune System Mediate the Resolution of Inflammation

Abstract

The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer's disease, and obesity in animal models. Finally, novel specialized proresolving mediators-eicosanoids with critical roles in resolution-may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor.

Figure 1

Inflammation and resolution are active and dynamic processes. The initiation, progression, and resolution of inflammation are characterized by unique cellular signals and trafficking.

Figure 2

Overview of PPARγ activation. PPARγ typically exists as a heterodimer with RXRα, bound to corepressor molecules. Upon ligand stimulation, these corepressors are displaced and the ligand, PPARγ, RXRα, and coactivators (such as CBP and SRC1) form an active complex, binding to PPARγ response elements (PPRE). Alternatively, upon ligand stimulation PPARγ alone can bind with NF-κB to repress NF-κB target genes.

Figure 3

PPARγ and macrophage activation. Proinflammatory macrophages are characterized by M1 activation markers, production of proinflammatory cytokines, and increased recruitment of immune cells. Upon stimulation with PPARγ ligands and/or increases in PPARγ expression, macrophages shift to an alternative M2 phenotype, with decreased proinflammatory actions, increased efferocytosis and phagocytosis, and production of anti-inflammatory cytokines.

Figure 4

PPARγ and platelet function. Upon stimulation with PPARγ ligands, platelets decrease expression of multiple proinflammatory proteins and lipids, including PAI-1, CRP, and TxB2. PPARγ ligands also decrease expression of P-selectin and CD40L, thereby decreasing the number of proinflammatory platelet/leukocyte aggregates.

Figure 5

PPARγ and the resolution of inflammation. PPARγ and PPARγ ligands (denoted by green diamond) play roles in all stages of inflammation. Early on, PPARγ and its ligands decrease neutrophil recruitment and proinflammatory cytokine production. PPARγ and its ligands then act to promote neutrophil apoptosis and efferocytosis and induction from proinflammatory to anti-inflammatory production. Finally, macrophages move to an M2 phenotype and tissue repair is initiated to return to homeostasis.