Introduction

The peroxisome proliferator-activated receptor (PPAR) was identified in the early 1990s as the target of compounds that cause proliferation of peroxisomes in rodent liver (Issemann and Green, 1990). Three PPAR isotypes were then identified in rodents, frogs, fishes, and humans, named PPAR (NR1C1), PPAR/ (NR1C2, called PPAR herein) and PPAR (NR1C3) (Desvergne and Wahli, 1999). They are ligand-induced transcription factors belonging to the nuclear hormone receptor superfamily that also includes, amongst others, retinoid X receptors, the vitamin D receptor, thyroid hormone receptors, and estrogen receptors.

PPARs are considered to be sensors, especially for polyunsaturated fatty acids and diverse fatty acid derivatives (Forman et al., 1997; Kliewer et al., 1997; Krey et al., 1997). Polyunsaturated fatty acids like arachidonic acid or linoleic acid are potent activators of the three PPARs. Arachidonic acid derivatives such as leukotrienes and prostaglandins are PPAR agonists that show higher selectivity towards PPAR, PPAR, and PPAR, respectively (Kersten and Wahli, 2000). In addition, several synthetic marketed drugs are PPAR ligands, such as the fibrates used to treat dyslipidemia through PPAR activation, and the antidiabetic thiazolidinediones that activate PPAR.

From a structural point of view, PPARs display the characteristic organization of nuclear receptors. The N-terminal A/B domain containing a putative ligand independent transactivation function (AF-1) is flanked by the C-domain which binds DNA via a two zinc finger motif. The C-domain is linked by a short hinge domain (D) to the C-terminal ligand-binding domain, also called the E/F domain, which contains the ligand-dependent transactivation function AF-2. In the PPAR and isotypes, the ligand-independent transactivation function can be regulated by phosphorylation via activation of the mitogen-activated protein kinase pathway (Diradourian et al., 2005; Gelman et al., 2005). Upon fixation of an agonist, a conformational change in the structure of the ligand-binding domain creates the interface required for interactions with coactivators, such as SRC-1 or CBP/p300, which results in the transactivation of target genes. Alternatively, PPARs can exert transrepression of gene activity via mechanisms that were reviewed recently (Feige et al., 2006).

Mainly expressed in the liver and brown adipose tissue, but also found at lower levels in the gut, muscle, and kidney, PPAR is involved in lipid catabolism (Kersten et al., 2000) and exerts anti-inflammatory effects (Delerive et al., 2001; Genolet et al., 2004; Kostadinova et al., 2005). Interestingly, PPAR is also expressed in the epidermis following a skin injury, as will be discussed below (Michalik et al., 2001). PPAR is involved in adipocyte differentiation and lipid storage, as well as in the control of inflammatory reactions. It is mostly expressed in adipose tissue, gut, and the immune system and is induced in the liver by a high-fat diet (Kersten et al., 2000). PPAR, which has remained the less understood isotype, displays an ubiquitous expression often at levels that are higher than those of the two other isotypes (Escher et al., 2001). Its upregulation in the murine interfollicular epidermis is of particular importance during skin wound healing (Michalik et al., 2001; Tan et al., 2001).

Ppar Expression In Healthy And Injured Skin

Single cell metabolism as well as intercellular interactions depend on complex mechanisms that ensure cell and tissue maintenance and renewal in a highly coordinated manner. The skin is a barrier against various environmental aggressions and dehydration, and is prone to be wounded. Following an injury and the inflammatory response it induces, repair is a survival process that involves activation of cells and their interactions with the extracellular matrix (ECM) to restore the integrity of the wounded area (Midwood et al., 2004). This repair is a life-saving priority process initiated by the disruption of the blood vessels that in turn triggers platelet activation and release of cytokines and growth factors. Immune cells invade the newly formed blood clot, and become involved in cell debris phagocytosis and the secretion of many inflammatory cytokines (Werner and Grose, 2003). This initial inflammatory stage is followed by the proliferative and migratory phases of the repair process. The proliferation of activated keratinocytes and their migration following directional sensing contribute to the re-epithelialization of the wound. In parallel, dermal repair involves recruitment and proliferation of fibroblasts – which produce extracellular matrix—and angiogenesis—which provides blood supply to the newly regenerated tissue. Fibroblasts also secrete growth factors stimulating re-epithelialization (Birch et al., 2005). Their differentiation into myofibroblasts allows wound contraction and tissue remodelling, the last steps in the wound-repair process (Desmouliere et al., 2005).

PPAR and PPAR expression is upregulated during the repair process, whereas PPAR remains undetectable in the wounded murine interfollicular epidermis. The upregulation of PPAR is transient and correlates with the inflammatory phase, while that of PPAR lasts over the entire healing process. The absence of PPAR in PPAR-null mice results in only a transient delay in wound repair, whereas completion of wound closure in animals lacking PPAR is retarded for 2–3 days (Michalik et al., 2001).

Ppar And Ppar Are Important Players In The Keratinocyte Response To Skin Injury

As mentioned above, the kinetics of wound closure in PPAR null mice reveal no overall delay in healing. However, during the first 4 days following an injury a transient delay coinciding with the inflammatory phase is observed, but later on normal wound-healing efficiency is restored. Monitoring inflammatory cell infiltration revealed an impaired recruitment of neutrophils and monocytes/macrophages to the wound bed in PPAR^-/- animals (Michalik et al., 2001). Transgenic mice expressing a dominant-negative form of PPAR in the epidermis (PPAR13) were used to determine whether this observation is the consequence of the genetic ablation of PPAR in immune cells and fibroblasts, or arises from a defect in keratinocytes. Interestingly, the PPAR13 mice displayed the same pattern in wound closure as the PPAR^-/- mice, with a transient delay in repair overlapping with the inflammatory phase (Michalik et al., 2005). No defect in immune cell recruitment was observed in these mice. However, an increase in the expression of tumor necrosis factor (TNF)- indicated that the inflammatory reaction is exacerbated in PPAR13-wounded skin. This revealed a loss of control of the inflammatory process in the transgenic animals.

The upregulation of PPAR expression in wound healing is correlated to keratinocyte proliferation, adhesion, and migration upon the extracellular matrix in order to re-epithelialize the wounded region. Consistent with this, the delay observed in wound repair of PPAR^+/- mice overlaps with these healing phases. The key molecular processes responsible for PPAR upregulation in keratinocytes were elucidated using primary keratinocyte cultures and a conditioned medium to mimic the inflammatory phase of wound repair (Tan et al., 2001). Following the release of pro-inflammatory cytokines such as TNF-, the stress-associated protein kinase pathway is activated, leading to the stimulation of PPAR expression through AP-1 binding to its promoter. In parallel, activation of the primary keratinocytes by pro-inflammatory cytokines triggers the production of an endogenous ligand for PPAR (Tan et al., 2001). PPAR then plays the role of a key transcription factor relaying inflammatory signals into cellular responses such as inflammation-induced differentiation, control of proliferation and resistance to apoptosis in keratinocytes. In the wound-healing process, PPAR promotes cell survival through a direct activation of the genes coding for integrin-linked kinase and 3-phosphoinositide-dependent kinase-1, and consequent activation of the PKB/Akt1 kinase (Di-Poi et al., 2002). In addition, PPAR is implicated in cell adhesion and migration as reflected by defects seen in the primary keratinocyte cultures (Tan et al., 2001).

Using an apoptotic-derived conditioned medium that mimics the late re-epithelialization or remodelling stages of wound healing, we have identified transforming growth factor (TGF)-1 as the cytokine that antagonizes TNF--induced PPAR expression in keratinocytes (Tan et al., 2004). This inhibitory effect occurs through the interaction of c-JUN with Smad3 (a downstream effector of TGF-1 signalling), preventing the binding of c-JUN-p300 to the AP-1 site in the PPAR promoter. Interestingly, both TNF- induction of PPAR expression, and its downregulation by TGF-1 converge on the same AP-1 response element, either bound by or depleted of c-jun. A prolonged expression of PPAR obtained through genetic ablation of Smad3 (Smad3^-/-) (Ashcroft et al., 1999), or through early treatment with TGF-1 (day 0) accelerates skin wound closure (Tan et al., 2005) (Figure 1). In agreement with the sustained expression of PPAR during wound closure, a prolonged increase of PKB/Akt1 activity was also observed in these conditions. According to the role of TGF-1 as a chemo-attractant for macrophages and neutrophils (Wahl et al., 1987), an increase in the number of recruited macrophages into the wound bed was observed in the animals treated with TGF-1 on the day of injury, compared to vehicle-treated animals (Tan et al., 2005). Therefore, we propose that early recruited macrophages produce a sufficient amount of inflammatory cytokines to overcome the inhibitory effect of TGF-1 on PPAR expression, and upregulate its expression as previously described (Tan et al., 2001). Conversely, exogenous application of TGF-1 on a skin wound at day 2 following the injury had opposite effects, with PPAR expression prematurely downregulated (Figure 1). As a consequence there was a decrease in PKB/Akt1 activity and a transient but significant delay in wound closure (Tan et al., 2005).

Figure 1.

Overview of the consequences of the crosstalk between PPAR and the TGF-1 pathway in skin repair. Upon injury pro-inflammatory cytokines such as TNF- are produced by the infiltrating immune cells contributing to PPAR re-expression in the interfollicular epidermis through an AP-1 response element in PPAR promoter (Tan et al., 2001). Activated PPAR regulates the expression of integrin-linked kinase and 3-phosphoinositide-dependent kinase-1, which contributes to PKB/Akt1 activation by phosphorylation to protect keratinocytes from apoptosis (Di-Poi et al., 2002). Along with the wound-repair progression into the re-epithelialization and remodelling phase, both wound fibroblasts and immune cells produce TGF-1. Through the activation of the TGF-1/Smad3 pathway, TGF-1 antagonizes the TNF- effect by preventing the binding of cJUNp300 on the AP-1 site in the PPAR promoter (Tan et al., 2004). As illustrated in the graphic representation of wound closure, delayed repression of PPAR expression obtained through genetic ablation of Smad3 accelerates wound healing, whereas its inhibition following topical application of TGF-1 at day 2 after injury leads to a transient delay in wound closure. Alternatively, early exposure to TGF-1 at day 0 following injury leads to a prolonged expression of PPAR and accelerated wound repair probably due to increased recruitment of inflammatory cells by TGF-1. Blue lines represent the kinetics of wound closure, red lines represent PPAR expression. Gray lines on each graph are a reminder of the wild-type pattern of both PPAR expression and kinetics of wound closure.

Full figure and legend (152K)

In summary, spatial and temporal effects mediated by cytokines modulate the response of keratinocytes during a stress situation such as skin injury. Cytokines, such as TNF- and TGF-1, are mainly produced by the cells populating the wound bed. They attract and activate surrounding keratinocytes that proliferate and migrate through the provisional matrix temporarily deposited in the clot. Activated keratinocytes produce TNF- that stimulates the expression of PPAR via the SAP-kinase pathway, until TGF-1 antagonizes this effect and suppresses PPAR expression. This temporal regulation is a key process in regenerating epithelium.

Involvement Of Ppar In Hair Follicle morphogenesis

When reactivated in interfollicular epithelium following injury, PPAR plays important roles in the response of keratinocytes to stress. In the hair follicle, PPAR is constitutively expressed, and, like many other nuclear hormone receptors, has a role in normal hair follicle development (Michalik et al., 2001; Alonso and Rosenfield, 2003; Di-Poi et al., 2005). Hair follicle morphogenesis depends on epithelium–mesenchyme interactions (Alonso and Rosenfield, 2003) and on hormonal signalling, which is important in modulating hair cycling from anagen to telogen. PPAR regulates postnatal hair growth, but not the initiation of hair morphogenesis, as the total number of hair follicles is similar in PPAR^+/+ and PPAR^-/- mice (Di-Poi et al., 2005). However, a lower hair score for hair follicle morphogenesis in PPAR^-/- compared to PPAR^+/+ mice showed that PPAR is required for hair follicle growth. In agreement with this observation, treatment of skin organ cultures with a PPAR agonist increases the hair score in PPAR^+/+ but not in the PPAR^-/- explants. Developing hair follicles of PPAR-deficient mice at postnatal day 4 (P4) display an increased amount of apoptotic keratinocytes compared to their wild-type counterparts, in which apoptotic keratinocytes are restricted to the suprabasal layers of the interfollicular epidermis (Figure 2b). Consistent with the known function of PPAR in regulating the activity of PKB/Akt1 (Di-Poi et al., 2002), and with the role of PKB/Akt1 in hair follicle morphogenesis (Rosenfield et al., 2000), the spatio-temporal activation of PPAR in the developing hair follicles protects keratinocytes from apoptosis via the PKB/Akt1 pathway. PKB/Akt1 activity in PPAR^+/+ skin is reflected in the increase of the phosphorylation of antiapoptotic factors, such as FKHR and Bad. In PPAR^-/- skin, this activation is postponed until P7. These data show that the delay in hair follicle morphogenesis seen in the skin of PPAR^-/- mice is the consequence of a reduced antiapoptotic activity of PKB/Akt1. In addition, a slight decrease in the number of proliferative cells was also observed in the PPAR^-/- mice compared to the wild-type skin.

Figure 2.

PPAR in hair follicle morphogenesis. (a) PPAR is constitutively expressed in hair follicles. It is transiently activated by ligands produced during hair follicle morphogenesis via COX-2 activation. COX-2 is activated in hair follicle keratinocytes via the paracrine effect of hepatocyte growth factor (HGF) through its receptor Met. (b) As described for wound repair, PPAR expression and activation during morphogenesis protects hair follicle keratinocytes from apoptosis. The TUNEL assay revealed an increased number of apoptotic cells in developing hair follicles from PPAR^-/- mice (day 4 postnatal P4, hair follicles at stage 1–4 according to the classification by Paus et al., 1999). (c) Quantification of proliferative and apoptotic cells in developing hair follicles at day P4: PPAR^-/- hair follicle keratinocytes, compared to their wild-type counterparts display less proliferation and increased apoptosis as revealed by proliferating cell nuclear antigen (PCNA)/5-bromodeoxyuridine staining (BrdU) and TUNEL assay, respectively.

Full figure and legend (128K)

Although PPAR is expressed constitutively in hair follicles at all stages of their morphogenesis, it seems to be important only for hair follicle elongation (P4), which suggests that a PPAR ligand is produced at that time. Cyclooxygenase-2 (COX-2) is known to produce arachidonic acid derivatives that are potent ligands of PPAR. Moreover, COX-2 was shown to be active in the developing hair follicles (Muller-Decker et al., 2003), where its stimulation parallels the action of PPAR. In fact COX-2 expression is upregulated in hair follicle keratinocytes from P1 to P4 by dermal signals produced by the dermal papilla (Millar, 2002; Zeng et al., 2002). In line with this expression pattern, the COX-2-specific inhibitor (NS-398) delays hair follicle morphogenesis in a dose-dependant manner when applied to PPAR^+/+ but not to PPAR^-/- skin explants (Di-Poi et al., 2005). Moreover, hepatocyte growth factor treatment increases COX-2 expression in both PPAR^+/+ and PPAR^-/- keratinocytes in a dose-dependent manner. Importantly, exposure of PPAR^+/+ keratinocytes to hepatocyte growth factor leads to an increase in the activity of PPAR, as reflected by increased expression levels of 3-phosphoinositide-dependent kinase-1 and integrin-linked kinase, and increased phosphorylation of PKB/Akt1 (Di-Poi et al., 2005).

In summary, hepatocyte growth factor produced by the dermal papilla fibroblasts triggers a temporal induction of COX-2 activity in hair follicle keratinocytes. COX-2 in turn activates PPAR via ligand production. The subsequent activation of the PKB/Akt1 pathway protects hair follicle keratinocytes from premature apoptosis, thus enabling them to participate in normal hair follicle morphogenesis (Di-Poi et al., 2005) (Figure 2).

Conclusion

The expression pattern of PPAR and PPAR in mouse epidermis suggests a dual role for these nuclear hormone receptors involved both in skin development and in repair after an injury. While both receptors are constitutively expressed in the hair follicles, they remain undetectable in the normal adult mouse interfollicular epidermis, in contrast to their expression in the embryonic epidermis. A full thickness injury of the adult skin induces a strong re-activation of PPAR and PPAR expression in these cells.

Genetically engineered PPAR^-/-, PPAR13, PPAR^+/-, and PPAR^-/- mice were valuable tools in deciphering the roles of PPAR and PPAR in the mechanisms of skin wound repair. PPAR^-/- and PPAR13 mice display a transient delay in wound closure that overlaps with the inflammatory phase of healing. This delay correlates with the impaired recruitment of inflammatory cells to the wound bed of injured PPAR^-/- mice. It is most probably due to a keratinocyte-dependent defect since it was also observed in PPAR13 mice that present an exacerbated production of TNF- after an injury. These two observations converge in suggesting an impaired inflammatory response in both types of mutant animals. They lend support to the notion that PPAR controls the inflammatory phase of skin repair. TNF- was found to be the trigger of inflammation-induced expression and activation of PPAR in the wounded epithelium via both the activation of the AP-1 transcription factor complex that binds to a response element in a PPAR promoter, and the production of an endogenous PPAR ligand. An opposing signal from the TGF-1 pathway converges at the same AP-1 response element leading to a decrease in PPAR expression at the later stages of repair. During the window of PPAR expression and activation controlled by the timely secretion of TNF- and TGF-1 by immune cells and myofibroblasts, respectively, keratinocytes are protected from cell death via the activation of the PKB/Akt1 pathway.

In addition to this stress response, epithelial–mesenchymal interactions are also involved in the mechanisms of hair follicle development. During hair follicle morphogenesis, fibroblasts from the dermal papilla produce the paracrine growth factor hepatocyte growth factor to which hair follicle keratinocytes respond by stimulation of the COX-2 gene. Enhanced COX-2 levels lead to increased PPAR ligand production. In this case, timely activation of the constitutively expressed PPAR induces the PKB/Akt1 pathway that protects follicular keratinocytes from premature apoptosis. In conclusion, PPAR and PPAR are key regulators of skin homeostasis. They control repair after an injury, and participate in normal hair follicle morphogenesis.

Conflict Of Interest

The authors state no conflict of interest.

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Acknowledgements

We thank Nicolas Di-Poï and Nguan Soon Tan for sharing results. The work carried out in the authors' laboratory was supported by grants from the Swiss National Science Foundation and the Etat de Vaud (W.W.).