Heme Catabolic Pathway in Inflammation and Immune Disorders

Abstract

In recent years, the heme catabolic pathway is considered to play an important regulatory role in cell protection, apoptosis, inflammation, and other physiological and pathological processes. An appropriate amount of heme forms the basic elements of various life activities, while when released in large quantities, it can induce toxicity by mediating oxidative stress and inflammation. Heme oxygenase (HO) -1 can catabolize free heme into carbon monoxide (CO), ferrous iron, and biliverdin (BV)/bilirubin (BR). The diverse functions of these metabolites in immune systems are fascinating. Decades work shows that administration of degradation products of heme such as CO and BV/BR exerts protective activities in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS) and other immune disorders. This review elaborates the molecular and biochemical characterization of heme catabolic pathway, discusses the signal transduction and immunomodulatory mechanism in inflammation and summarizes the promising therapeutic strategies based on this pathway in inflammatory and immune disorders.

Keywords: biliverdin; carbon monoxide; heme; heme oxygenase; immune disorders; inflammation.

Figure 1

Heme metabolic pathway. Heme oxygenase (HO) catabolizes free heme into biliverdin (BV), carbon monoxide (CO) and Fe²⁺. Biliverdin (BV) is transformed into bilirubin (BR) by biliverdin reductase (BVR) enzyme. Fe²⁺ can be bound by the iron storage protein ferritin. The heme molecule provides a multitude of crucial biological functions in the form of various apo-heme proteins like hemoglobin, nitric oxide synthase, and cytochromes. HO-1-derived metabolite CO could exert anti-inflammatory, anti-proliferation, anti-apoptosis and vasodilation effects in immune system. Similarly, BR could play a key role in anti-inflammation, anti-proliferation, anti-apoptosis, anti-oxidation and free radical scavenger. Additionally, iron-induced ferritin could play a cytoprotective, anti-oxidative and iron storage effect. Notably, HO-1 and serum BR/BV can be used as biomarker for autoimmune diseases. While, the potential of serum ferritin as a biomarker in systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) diagnosis process needs further verification. Serum ferritin levels are positively correlated with disease activity index in SLE and RA patients. In addition, the serum levels in patients with SLE and RA are lower than healthy controls and were inversely correlated with disease severity. In inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE) diseases, the level of HO-1 in lesions rises along the disease course, and the induction of HO-1 could improve diseases severity.

Figure 2

Pivotal functions of the molecules in heme metabolic pathway in inflammation. Free heme is transported by an unknown transporter into intracellular side. Heme can activate spleen tyrosine kinase (Syk) and subsequently induce reactive oxygen species (ROS) generation. Furthermore, heme can activate Toll-like receptor4 (TLR4) inducing ROS production dependent on NADPH oxidase and promoting proinflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α)] generation. HO-1 have immunomodulatory effects in dendritic cells (DCs), antigen-presenting cells (APCs) and regulatory T cells. In heme metabolic pathway, the end product ferrous iron (Fe²⁺) is proinflammatory and could be sequestered by iron storage protein ferritin. The ferritin inhibits interleukin-2 (IL-2) and IgG production. In addition, it is involved in mitogen-activated protein kinase (MAPK) signaling pathway. CO downregulates the production of proinflammatory cytokines (e.g., TNF-α, IL-6) and upregulates the anti-proinflammatory cytokines (e.g., IL-10) relating to MAPK signaling pathway. CO inhibits ROS generation and regulates inflammasome activation followed by impacting IL-1β maturation and secretion. Of note, CO could augment the interaction between caveolin-1 (cav-1) and TLR4 suppressing TLR4-mediated signaling. BV/BR exerts anti-inflammatory and anti-oxidant effects about innate and adaptive immunity. The production of pro-inflammatory cytokine TNF-α can be secreted into extracellular side. TNF-α binds to its receptor inducing necrosis mediated by receptor-interacting protein (RIP1/3).

Figure 3

Therapeutic strategies are involved in heme metabolic pathway. strategies include extracellular and intracellular ways. Extracellular mechanisms mainly conclude scavenger proteins haptoglobin (Hp)/hemopexin (Hx) binding hemoglobin (Hb)/free heme respectively. Furthermore, albumin binds free heme inhibiting its proinflammatory effects. Hp-Hb complex binds to CD163 receptor expressed on the cell membrane, leading to endocytosis and degradation of the Hb and Hp complexes. It is noteworthy that CO binding Fe²⁺ in hemoproteins could prevent heme releasing. Heme-Hx complex is recognized by cell receptor CD91, delivering heme for catabolism by HO-1. The intracellular heme is degraded by HO-1. In addition, cellular heme levels could be excluded by heme efflux transporters FLVCR and Bcrp/Abcg2. Gene therapy and HO-1 inducers could regulate HO-1. HO-1 inducers contain natural (polyphenols) and synthetic (DMF) compounds. In addition, as the substrate of HO-1, hemin is a natural HO-1 inducer existing in human body. The labile ferrous iron released from heme catabolism is subsequently sequestered by ferritin, thus conferring cyto-protection against heme-Fe²⁺. The end products of HO-1 activity, namely BV/BR, and CO act as pharmacologic molecules. CO could be elevated by inhalation or through the use of CO-releasing molecules (CORMs). Additional therapy involving CO includes CO-binding hemoglobins. BV/BR treatment and BVR expression is also proposed as intervention strategies.