An inflammatory triangle in Sarcoidosis: PPAR-γ, immune microenvironment, and inflammation

ABSTRACT

Introduction

Sarcoidosis is an inflammatory disorder characterized by granuloma formation in several organs. Sarcoidosis patients experience higher inflammatory responses resulting in pulmonary fibrosis. Although the precise mechanisms have not been well elucidated, the relationship between the immune system activation and inflammatory status is pivotal in the pathogenesis of sarcoidosis.

Areas covered

Peroxisome proliferator-activated receptor (PPAR) includes the transcription factors involved in cell metabolism, proliferation, and immune response. In the alveolar macrophages of patients with sarcoidosis, the reduced activity and a decreased level of PPAR-γ have been shown. In this study, we discuss how reducing the level of PPAR-γ could lead to increased inflammation and immune responses in patients with sarcoidosis.

Expert opinion

Lack of PPAR-γ may contribute to the development of a suitable milieu for the formation of immune-associated pulmonary granuloma. Reduced levels of PPAR-γ in sarcoidosis could result from over-activation of the immune system and elevated inflammatory responses, as well. Due to the anti-inflammatory function of PPAR-γ, identifying the relation between PPAR-γ, sarcoidosis development, and inflammatory state could be essential to identify the appropriate therapeutic targets. The synthesis of PPAR-γ agonists or PPAR-γ ligands may be an effective step toward the treatment of sarcoidosis patients in the future.

KEYWORDS:

• Pulmonary sarcoidosis
• peroxisome proliferator-activated receptor gamma
• ppar-γ
• alveolar macrophages
• fibrosis
• inflammation

Article highlights

• Immune system overactivation plays a pivotal role in the pathogenesis of sarcoidosis. The immune system initiates responding with antigen-presenting cells (APCs), especially alveolar macrophages (AMs) in the lungs.

• The relationship between the immune system, inflammation, and the reduced levels of PPAR-γ could be considered as a reinforcing loop to increase the pathogenesis of sarcoidosis patients.

• PPAR-γ keeps pulmonary lipid homeostasis stable. Lack of PPAR-γ could lead to developing a suitable milieu for the formation of immune-associated pulmonary granuloma through impairing the clearance of foreign antigenic peptides in the lung, increased phagocytosis, consistent rising of T helper lymphocytes and Th17 cells activation

• Reduced levels of PPAR-γ in sarcoidosis could result from over-activation of the immune system and elevated inflammatory responses.

• PPAR-γ agonists contribute to the regulation of epithelial cell inflammation and fibrosis by reducing the production of TNF-α and mucin, PTEN up-regulation, MMPs down-regulation.

List of abbreviations

APC: antigen-presenting cellAM: alveolar macrophagesANXA11: Annexin A11AMT: amoeboid-mesenchymal transitionABCG1: ATP-binding cassette lipid transporter-G1BTNL2: Butyrophilin Like 2BALF: Bronchoalveolar Lavage FluidCCL18: CC chemokine ligand 18EMT: epithelial-mesenchymal transitionEndoMT: endothelial-mesenchymal transitionFPRL1: formyl peptide receptor like 1GM-CSF: Granulocyte-macrophage colony-stimulating factor,HLA: human leukocyte antigenHGF: hepatocyte growth factorIFN-γ: interferon-gammaiNOS: inducible nitric oxide synthaseIL: interleukinIL23r: interleukin-23 receptorMMPs: Matrix MetalloproteinaseMCP-1: Monocyte Chemo attractant Protein-1NOTCH4: Notch Receptor 4PPAR: peroxisome proliferator-activated receptorsPPRE: PPAR response elementsPTEN: Phosphatase and tensin homologRAGE: receptor for advanced glycation end productsRXRs: retinoid x receptorsSAA: serum amyloid ATNF: tumor necrosis factorTregs: regulatory T cellsTLR: toll-like receptorXAF1: X-linked Inhibitor of Apoptosis Associated Factor 1XIAP: X-linked inhibitor of apoptosis protein

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.