Journal Article

Effect of heme oxygenase-1 on the expression of interferon-stimulated genes

Bednarczyk, Katarzyna, Szade, Agata, Szade, Krzysztof, Wolnik, Jan, Krzeptowski, Wojciech, Żukowska, Monika, Chudy, Patryk, Chatian, Eryk, Nowak, Witold N., Sokołowski, Grzegorz, Grochot-Przęczek, Anna, Józkowicz, Alicja

2025

Overview

Heme oxygenase-1 (HO1, Hmox1 ) degrades excess heme and is considered an anti-oxidative and anti-inflammatory enzyme. Our previous studies in Hmox1 knockout mice revealed the induction of interferon-stimulated genes (ISGs) in all cell types analyzed, despite unchanged interferon production. Here, we sought to determine whether this induction is driven by intrinsic cellular mechanisms or extrinsic cues at the organismal level, and to identify the pathway underlying HO1-dependent ISG regulation. To this end, we analyzed how ISG expression changes in cultured cells exposed to stressors typical of Hmox1 knockout mice. Using murine wild-type and Hmox1 -deficient (Hmox1 KO) fibroblasts, we found that under control conditions, the expression of most tested ISGs was independent of cellular HO1 status. We next examined the effects of extrinsic stressors, including hemolytic, oxidative, genotoxic, and replication stress, proinflammatory TNFα, and endogenous heme overload. TNFα, which is upregulated in Hmox1 knockout mice, was the sole and universal inducer of ISGs in both wild-type and Hmox1 KO fibroblasts. Unexpectedly, the response of Hmox1 KO cells to exogenous TNFα was weakened, likely due to impaired NF-κB activity and reduced nuclear retention of the p65 subunit. A similar decrease we observed for STAT1. Additionally, the presence of the TREX1 exonuclease in the nucleus pointed to compromised nuclear envelope integrity in HO-deficient cells. Notably, HO1 colocalizes with PARP1, a protein involved in envelope maintenance and regulation of cytoplasmic-nuclear transport. Inhibition of PARP1 with olaparib dampened TNFα-induced nuclear accumulation of p65 and STAT1 in wild-type cells, but not in Hmox1 KO counterparts. In summary, the inflammation observed in Hmox1 -deficient mice appears to be the main cell-extrinsic driver of ISG induction in vivo. Despite this, the inflammatory response to exogenous TNFα is intrinsically attenuated in Hmox1 KO cells, likely due to decreased nuclear retention of NF-κB and STAT1.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Allergology / Biological response modifiers / Biomedical and Life Sciences / Biomedicine / Cytokines and Growth Factors / Enzymes / Ethylenediaminetetraacetic acid / Gastroenterology / Genes / Heme / Immunology / Inflammation / Interferon / Pharmacology/Toxicology / Rheumatology