Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

Abstract

SummaryHaem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC-and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases.

Modulation of Antiviral Immunity by Heme Oxygenase-1

“…12 In a steady state, the expression of HO-1 is suppressed by the repressor protein Bach1, which heterodimerizes with MAF to bind DNA, specifically at an antioxidant responsive element in the Hmox1 gene promoter ( Figure 1A). 13 At the same time, Nrf2 forms a complex with Keap1 in the cytoplasm, with Keap1 promoting the proteasomal degradation of Nrf2 ( Figure 1A). 13 Upon cellular stress, such as during proinflammatory stimuli or the presence of heme analogs, the Nrf2 protein dissociates from Keap1 and is phosphorylated by protein kinases, which induce its translocation to the nucleus.…”

“…13 At the same time, Nrf2 forms a complex with Keap1 in the cytoplasm, with Keap1 promoting the proteasomal degradation of Nrf2 ( Figure 1A). 13 Upon cellular stress, such as during proinflammatory stimuli or the presence of heme analogs, the Nrf2 protein dissociates from Keap1 and is phosphorylated by protein kinases, which induce its translocation to the nucleus. During this process, the Bach1-MAF complex dissociates and free MAF now interacts with Nrf2 to form a transcriptionally active complex that promotes the transcription of Hmox1 ( Figure 1B).…”

“…During this process, the Bach1-MAF complex dissociates and free MAF now interacts with Nrf2 to form a transcriptionally active complex that promotes the transcription of Hmox1 ( Figure 1B). 13 In addition, HO-1 expression is also regulated in a posttranscriptional manner by miRNAs. 14 Indeed, studies performed in the context of an intravascular hemolysis model, showed that miR-377 and miR-217 interact with the Hmox1e3 0 -untranslated region, resulting in the reduction of HO-1 protein expression and, hence, reduced enzymatic activity.…”

Heme oxygenase 1 polymorphism, occupational vapor, gas, dust, and fume exposure and chronic obstructive pulmonary disease in a Danish population-based study

“…Heme oxygenase 1 (HMOX1) is an anti-oxidant and anti-inflammatory heme-degrading enzyme and the gene is known as a cytoprotective stress response gene (6)(7)(8). A dinucleotide repeat (GT) n sequence in the 5' of the promoter region of the HMOX1 gene (rs3074372) modulates gene expression.…”

“…A dinucleotide repeat (GT) n sequence in the 5' of the promoter region of the HMOX1 gene (rs3074372) modulates gene expression. A long allele (many repeats) has been shown to reduce enzyme activity and associate with various diseases (8,9). Several studies have previously discussed whether this polymorphism affects COPD and impairs lung function yet with divergent outcomes and conclusions (4).…”