Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases

Abstract

Heme oxygenase (HO) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. Here we discuss some naturally derived compounds involved in HO-1 induction, their impact in the immune response modulation, and the beneficial effect in diverse autoimmune disorders. We conclude that the use of some compounds from natural sources able to induce HO-1 is an attractive lifestyle toward promoting human health. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity.

Immune Modulation by Inhibitors of the HO System

“…As described above, HO-1 plays a critical role at protecting the body from oxidative damage, which is supported by studies carried out in several inflammatory models [ 11 , 122 , 123 ]. Accordingly, HO-1-deficient mice are more susceptible to oxidant-induced tissue injury by endotoxin exposure [ 124 ].…”

“…Several studies have focused their attention on the anti-inflammatory and antioxidant properties of the products generated by the HO system, especially HO-1 since it is the inducible isoform [ 11 , 12 , 151 ]. However, as described in this revision, HO overexpression can also be detrimental to many pathologies.…”

“…Under specific conditions, such as cellular stress, HO-1 can be regulated by the antioxidant response element (ARE) located at the HO-1 gene promoter that binds to the nuclear factor erythroid 2-related factor 2 (Nrf2) and promotes the expression of this gene [ 18 ]; at the same time, levels of Nrf2 are directly controlled by NFκB expression, which is overexpressed during inflammatory processes [ 19 ]. Similarly, the activator protein 1 (AP-1) transcription factor responds to oxidative stimuli by binding to enhancers flanking the HMOX1 protomer region and increases HO-1 transcription in both immune and non-immune cells [ 11 ]. Signal transducer and activator of transcription 3 (STAT3) is another transcription factor able to promote HO expression [ 20 ].…”

“…As described above, the HO system catalyzes the degradation of the heme group, generating CO, biliverdin, and Fe 2+ as products [ 29 ]. Several studies have described some of these products as anti-inflammatory agents for many chronic and infectious diseases [ 10 , 11 , 12 , 30 ]. However, to understand the function of this enzymatic system, the identification and synthesis of inhibitory molecules were necessary [ 31 , 32 ].…”

“…It is thought that HO-3 is a retrotransposition (pseudogene) of the HO-2 gene [ 10 ]. Altered HO-1 expression is reported in many clinical conditions, such as autoimmune diseases [ 11 ], porphyria, obesity [ 12 ], cancer [ 8 , 13 ], and infection diseases, among others [ 12 ]. This article will focus on pathologies caused by the overexpression of HO-1 and how inhibitors can be beneficial due to their immunomodulatory activity.…”