Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-γ as Candidates for Cytokine Storm Modulation in COVID-19 Disease

Abstract

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.

Keywords: PPAR-γ; PPAR-γ agonists; coronavirus infection; cytokine storm; inflammation; metabolism.

Figure 1

Peroxisome proliferator-activated receptors (PPARs). (A) Schematic representation of functional domains in PPAR. AF-1: domain of activation function 1; DBD: DNA-binding domain; LBD: ligand binding domain; AF-2: domain of activation function 2. (B) Mechanism of PPAR-RXR signaling. Upon ligand binding, the heterodimer PPAR: RXR translocates into the nucleus, where it binds to target DNA in correspondence with peroxisome proliferator hormone response elements (PPREs). This step initiates structural alterations essential to target gene modulation by PPARs.

Figure 2

Chemical structure of representative TZDs and functions. (A) Chemical structure of pioglitazone (CID = 4829) and rosiglitazone (CID = 77999) [45]. (B) Schematic representation of TZD effects. The binding of TZDs, like pioglitazone and rosiglitazone, to PPAR-γ induces its activation, triggering the modulation of target gene expression and a broad range of mechanisms, including lipid metabolism, regulation of glucose levels, inflammatory processes, cell proliferation and migration, cardiovascular diseases and vascular remodeling, and cytokine storm occurrence under virus infections.

Figure 3

Effects of PPAR-γ activation on cytokine storm. The stimulation of PPAR-γ by drugs or foods can exert a regulatory role on the cytokine storm typical of virus infections. Pro-inflammatory cytokines (e.g., IFN, TNF-α, IL-1β) are released by lung-epithelial cells, endothelial cells, and immune cells, inducing the immune system response. This mechanism recruits chemokines and other cytokines, in a vicious circle out of control. PPAR-γ acts on the transcription of the upstream inflammatory genes, thus preventing the cytokine over-production and becoming an attractive target for immunomodulatory therapies in the case of viral infections.