Role of PPARα in the Gastrointestinal Mucosa: History
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Contributor:
Maja Grabacka
,
Przemysław M. Płonka
,
Małgorzata Pierzchalska

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed throughout the mammalian gut: in epithelial cells, in the villi of enterocytes and in Paneth cells of intestinal crypts, as well as in some immune cells (e.g., lamina propria macrophages, dendritic cells) of the mucosa.  The Ppara transcription quantification in villus-crypt axis showed that the highest expression is observed in the peaks of villi of the middle part between duodenum and ileum of murine intestine. 

  • peroxisome proliferator-activated receptor α
  • leaky gut syndrome

1. The Role of PPARa in Immunotolerance of Dietary Antigens

Enterocytes uptake and transcellularly transport antigens from intestinal lumen and can present antigens to lamina propria T cells, because they express low levels of MHC class II molecules on their basolateral membranes [1][2]. This process, important for the development of tolerance to dietary antigens and to host commensal microbiota, is also crucial to maintaining the balance between GALT tolerance vs. hypersensitivity or inflammation. The immune tolerance to orally administered antigens occurs through various routes, for instance through transforming growth factor β (TGFβ)-mediated suppression, clonal T cell deletion, or frequently clonal T cell anergy [3]. T cell anergy develops when APCs lack full range of costimulatory molecules on their surface, such as B7-1/2 (CD80/CD86), ICAM-1, etc. Enterocytes do not express these costimulatory molecules [4], so their engagement in the antigen presentation normally leads to anergy of naïve CD4+ T cells [3]. CD8+ and CD4+ T lymphocyte populations both take part in the suppression of immune response to oral antigens, which is mediated by the release of IL-4, IL-10 and TGFβ with simultaneous suppression of IFNγ secreting cells [5].
Dendritic cells (DCs), present in intestinal mucosa and Peyer’s patches, are professional APCs which, in cooperation with microfold cells (M cells), determine the GALT response to antigens: either tolerance or priming [6]. In healthy mucosa, DCs express low levels of B7-1 and CD40 costimulatory molecules and play a crucial role in the development of tolerance to soluble proteins and noninvasive microorganisms in GALT [3]. PPARα receptors are expressed at high levels in immature DCs [7]. PPARα activation by fenofibrate or Wy-16434 inhibits DCs maturation (regarded as the elevated expression of costimulatory molecule genes) and suppresses DCs effector functions, such as IL-12 production, in response to pro-inflammatory signals (e.g., lipopolysaccharide, LPS or oxidized low density lipoproteins, oxLDL), thus directing DCs into a less stimulatory phenotype [7][8]. Interestingly, fenofibrate inhibited monocyte differentiation into DCs and their T cell stimulatory functions [9]. This effect was manifested by morphological changes, such as reduction in the length and number of dendrites, as well as the suppressed expression of DCs maturation markers (genes encoding CD1a, CD40 and HLA-DR) and reduction in LPS or oxLDL-triggered IL-10 and IL-12 secretion [9]. In summary, PPARα activation may contribute to maintenance of tolerogenic behavior of DCs towards antigens from the diet or commensal microbiota.

2. The Role of PPARα in Pathophysiology of Colitis

Due to its anti-inflammatory and metabolic functions, PPARα is regarded as a valuable therapeutic target in chronic colitis in its various forms, such as inflammatory bowel disease (IBD): ulcerative colitis or Crohn disease (CD). Multiple studies demonstrated the involvement of PPARα in the alleviation of symptoms and histological hallmarks in animal models of these diseases [10][11]. Recently, using an innovative artificial intelligence-based approach, Katkar and co-authors have designed and synthesized a dual PPARα/PPARγ agonist PAR5359 and proved it to be an effective candidate to treat IBD [12]. In their work, Boolean Network explorer (BoNE) computational tool was used to analyze multiple transcriptomic datasets (derived from healthy human colon, ulcerative colitis and CD samples, as well as normal murine gut and mouse colitis samples) to reveal a severe downregulation of PPARα and γ genes, as well as their signaling pathways in IBD. This discovery served to predict that simultaneous activation of PPARα and γ would decrease inflammation, tissue damage and fibrosis and help to restore the epithelial barrier [12]. Despite contradictory evidence in the literature regarding the role of PPARα and its agonists in IBD models (i.e., protective role confirmed in spontaneous model of colitis in IL-10 −/− mice [13]; in dextran sulfate sodium (DSS)-induced colitis [10][11][14][15]; in dinitrobenzene sulfonic acid (DNBS)-induced colitis [16]; but the disease exacerbation was documented by [17][18][19]), the computational approach suggested that the activation of both PPARα and γ receptors in the immune target cells, such as macrophages and DCs, would be beneficial through calming down the inflammation with simultaneous support of an adequate level of immune response [12]. The protein-protein interactome (PPI) analysis in silico indicated that PGC-1α would be a common interactor between PPARα and γ after using a double ligand. Notably, both PPARα and PGC-1α are necessary for the therapeutic effect of infliximab (a chimeric monoclonal IgG1 antibody against TNF), a golden standard drug effective in patients with moderate or severe IBD [11][20]. In the animal IBD model, the double PPARα/γ agonist PAR5359 significantly alleviated both Citrobacter rodentii- and DSS-induced colitis. This compound effectively reduced fecal bacteria load, leukocyte infiltration in the colon and the associated tissue damage. These results indicated a rapid clearance of pathogens and well-resolved inflammation, neither of which were seen in mice treated with a single PPARα or γ agonist [12]. PAR5359 was also effective in the alleviation of clinical and histological parameters of severity in DSS-induced colitis. Importantly, the simultaneous activation of both PPARα and PPARγ helped to preserve the expression of epithelial tight and adherens junction genes and achieve a proper balance of macrophage inflammatory and pro-resolving functions (M1/M2 gene signatures) [12]. The authors concluded that single PPARγ activation suppressed destructive inflammation but did not overcome the infection, whereas single PPARα activation supported pathogen elimination, but was not sufficient in resolving the inflammation.

3. The Role of PPARα in the Production of Antimicrobial Peptides and Paneth Cell Functions

The mucosal immune functions are supported by anti-microbial peptides, such as defensins. These peptides not only protect epithelium from pathogenic microbial insults but are also able to modulate functions of immune effector cells, such as macrophages. PPARα agonists, fenofibrate and gemfibrozil, dose-dependent induced expression of β-defensin 1 encoding gene in LPS-stimulated macrophages, while simultaneously downregulating Toll-like receptor 4 (TLR4), pro-inflammatory NFκB and Erk signaling, as well as chemokine CXCL2 and cytokine TNFα and IL-6 [21]. Surprisingly, these effects depended on the presence of β-defensin 1: siRNA-mediated knockdown of DEFB1 gene abolished the anti-inflammatory action of PPARα agonists [21]. This mechanism involved a kind of an autocrine regulation because IP-depletion of β-defensin from the macrophage conditioned media abrogated the effect of gemfibrozil and fenofibrate.
PPARα involvement in β-defensin 1 gene expression is likely to be mediated by peroxisome proliferator response elements (PPRE) found in DEFB1 gene [22]. These PPRE elements were proposed to act with PPARγ, which contribute to the proper anti-bacterial response in the colon [22]. Nevertheless, anti-microbial immunity in ileum does not depend on PPARγ [22], and PPARα seems to be a natural candidate here.
Alpha and beta defensins are important components of the innate anti-microbial defense, but the study by Ann et al. [21] suggest their broader immunoregulatory role. The main source of anti-microbial peptides in the small intestine are Paneth cells, which produce α-defensin (called cryptidin in mice), lysozyme, matrix metalloproteinase 7 and phospholipase PLA2G2 [23]. Paneth cells are important not only for bactericidal innate immunity, but also create a niche for intestinal stem cells (ISCs) in the crypts and support ISCs epithelial cell renewing potential. This latter role has been recently explored by Pentinmikko et al. [24], who discovered that a WNT inhibitor Notum, produced by Paneth cells in aged intestinal epithelium, impaired ICSs renewal and regenerating potential, both in human and murine intestines. The Paneth cell senescence leads to enhanced activity of mammalian target of rapamycin complex 1 (mTORC1), which is a known antagonist of PPARα [25]. Indeed, active mTORC1 signaling in ageing Paneth cells suppressed PPARα activity, which resulted in the increased secretion of Notum. Notum acts as a Wnt deacylase which induces dissociation of Wnt ligands (important for the maintenance of stemness) from LRP5/6-Frizzled receptors [24]. PPARα antagonist GW6471 was demonstrated to increase Notum secretion in ‘young’ Paneth cells, which led to a reduced regenerative potential of the intestinal mucosa [24]. Interestingly, a decline in fatty acid oxidation, a canonical PPARα-dependent metabolic pathway, is associated with an impaired ISCs function during aging [24]. These data indicate the indispensable role of PPARα in sustaining the renewal potential of ISCs niche in gut mucosa.
Paneth cell differentiation and bactericidal activity is also regulated by PPARβ [26]. This Ppard gene shows a particularly strong expression in the intestinal crypts, in the places occupied by Paneth cells. PPARβ activity is responsible for Paneth cell development and function through antagonism with Indian hedgehog signaling [26]. In the small intestine of PPARβ knock-out mice, there are significantly fewer Paneth cells than in wild type (wt) mice and they express lower levels of functional markers, such as α-defensin, lysozyme and MMP-7 (the enzyme necessary for activation of α defensins) and lysates from these intestines show reduced bactericidal activity towards Escherichia coli K12 [26]. Nevertheless, the abundance of bacterial populations of Enterobacteria, Staphylococci and Bacteroides sp. in the small intestines were similar in both Ppard +/+ and −/− mice. The significant differences in favor of wt mice were seen in case of Lactobacilli, but Bifidobacteria were more abundant in ileum of Ppard −/− mice [26]. These alterations in microbiota composition do not necessarily reveal the situation in the colon, because the small intestine microbiota is much less abundant and diverse in comparison to the colon [27]. Nevertheless, these results indicate potential involvement of PPAR receptors in the modulation of Paneth cell function, which in consequence affects various gut microbiota species.

This entry is adapted from the peer-reviewed paper 10.3390/ijms232214156

References

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