Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment

Abstract

The escalation in living standards and adoption of 'Western lifestyle' has an allied effect on the increased allergy and asthma burden in both developed and developing countries. Current scientific reports bespeak an association between allergic diseases and metabolic dysfunction; hinting toward the critical requirement of organized lifestyle and dietary habits. The ubiquitous nuclear receptors (NRs) translate metabolic stimuli into gene regulatory signals, integrating diet inflences to overall developmental and physiological processes. As a consequence of such promising attributes, nuclear receptors have historically been at the cutting edge of pharmacy world. This review discusses the recent findings that feature the cardinal importance of nuclear receptors and how they can be instrumental in modulating current asthma pharmacology. Further, it highlights a possible future employment of therapy involving dietary supplements and synthetic ligands that would engage NRs and aid in eliminating both asthma and linked comorbidities. Therefore, uncovering new and evolving roles through analysis of genomic changes would represent a feasible approach in both prevention and alleviation of asthma.

Keywords: asthma; comorbidities; diet; glucocorticoids; nuclear receptors.

Figure 1

Asthma, comorbidities and treatment challenges. (A) The link between asthma phenotypes and endotypes is depicted; suggesting possible existence of multiple endotypes for a single phenotype and vice-versa. The outer sphere portrays the commonly observed comorbid conditions in asthma patients. (B) The reported side-effects and shortcomings of glucocorticoid receptor and other adjunct therapies in asthma have been highlighted.

Figure 2

The protective effects of nuclear receptors (NRs) in asthma. Key mechanisms through which (A) Glucocorticoid receptor (B) Vitamin D receptor (C) Androgen receptor and Retinoic acid receptor-Retinoic X receptor (D) Nurr77, Farnesoid X receptor and Peroxisome proliferator-activated receptors provide protection against asthma have been summarized in a schematic form.

Figure 3

The exacerbating or promiscuous effects of nuclear receptors (NRs) in asthma. The influence of (A) Estrogen receptor and Progesterone receptor (B) Liver-X-receptor (C) Retinoic acid receptor-related orphan receptor alpha on major immunological pathways in asthma have been summarized in a schematic form.

Figure 4

Effects of nuclear receptors (NRs) on asthma comorbidities. The NRs are also known to impact asthma comorbidities; both protective and exacerbating roles have been documented. (A) The illustration depicts the reported roles of GR and adopted orphan/orphan receptors in various comorbid conditions. (B) A proposed hypothetical model of a cleaner therapeutic target as a remedy for asthma and associated comorbidities that can also maintain immune homeostasis.

Figure 5

Nuclear receptors (NRs) at the crossroads of asthma, comorbidities, diet and gut microflora. Numerous studies have highlighted the significant influence of diet, gut microflora and existing comorbidities in asthma pathogenesis and therapy outcomes. With reported roles of NRs in asthma and comorbidities along with its ability to crosstalk with diet, drugs and microflora, NRs become the strategic molecules for therapeutic intervention in asthma.