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Review
. 2020 Jul 14:11:1059.
doi: 10.3389/fphar.2020.01059. eCollection 2020.

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

Caterina Di Pietro  1 , Hasan H Öz  1 , Thomas S Murray  1 , Emanuela M Bruscia  1
Affiliations
Review

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

Caterina Di Pietro et al. Front Pharmacol. .

Abstract

In individuals with cystic fibrosis (CF), lung hyper-inflammation starts early in life and is perpetuated by mucus obstruction and persistent bacterial infections. The continuous tissue damage and scarring caused by non-resolving inflammation leads to bronchiectasis and, ultimately, respiratory failure. Macrophages (MΦs) are key regulators of immune response and host defense. We and others have shown that, in CF, MΦs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MΦs contribute to the inability of CF lung tissues to control the inflammatory response or restore tissue homeostasis. The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response, including the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway. HO-1 is an enzyme that degrades heme groups, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators, such as biliverdin, bilirubin, and CO. This pathway is fundamental to re-establishing cellular homeostasis in response to various insults, such as oxidative stress and infection. Monocytes/MΦs rely on abundant induction of the HO-1/CO pathway for a controlled immune response and for potent bactericidal activity. Here, we discuss studies showing that blunted HO-1 activation in CF-affected cells contributes to hyper-inflammation and defective host defense against bacteria. We dissect potential cellular mechanisms that may lead to decreased HO-1 induction in CF cells. We review literature suggesting that induction of HO-1 may be beneficial for the treatment of CF lung disease. Finally, we discuss recent studies highlighting how endogenous HO-1 can be induced by administration of controlled doses of CO to reduce lung hyper-inflammation, oxidative stress, bacterial infection, and dysfunctional ion transport, which are all hallmarks of CF lung disease.

Keywords: CO-releasing molecules; carbon monoxide (CO); cystic fibrosis (CF); heme oxygenase-1 (HO-1); lung inflammation; monocyte/macrophages.

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Figures

Figure 1
Figure 1
HO-1 enzymatic activity. HO-1 enzymatic activity generates biliverdin and releases carbon monoxide (CO) and Fe2+. Biliverdin is transformed into bilirubin by the biliverdin reductase (BVR). Fe2+ is sequestered by the iron storage protein ferritin.
Figure 2
Figure 2
Hmox1 transcriptional regulation. (A) At steady state, Nrf2 is bound to Keap1 in the cytoplasm and targeted for proteasomal degradation. Bach‐1 is bound to Maf at the promoter region of the hmox1, suppressing its transcription. (B) During cellular stress, hmox1 expression is activated in several ways: mitogen-activated protein kinase (MAPKs) and protein kinase C (PKC) phosphorylate Nrf2. This stabilizes Nrf2, leading to its translocation into the nucleus. PI3K/AKT inhibits GSK3β. When activated, GSK3β facilitates the ubiquitination and proteasomal degradation of Nrf2. Once in the nucleus, Nrf2 displaces Bach‐1 at the hmox1 promoter leading to transcription. (C) HIF-1 is a heterodimer composed of HIF-1α and HIF-1β. HIF-1α phosphorylation leads to its translocation to the nucleus and association to HIF-1β and CBP/p300, thus inducing hmox1 transcription. (D) Phosphorylation of c-Fos and c-Jun leads to their translocation to the nucleus and formation of the AP-1 complex, which induces hmox1 expression; (E) NF-κB is sequestered in the cytosol under basal conditions by the inhibitor IκB. Phosphorylation results in the proteasomal degradation of IĸB and the consequent release and nuclear translocation of NF-κB dimers (p50/p65) which targets hmox1 activation. A complex crosstalk between NF-κB and Nrf2 can also inhibit hmox1 transcription.
Figure 3
Figure 3
Mechanisms of HO-1 dysregulation in cystic fibrosis (CF). In the absence of functional CFTR: (A) MΦs have a blunted PI3K/AKT signaling in response to TLR4 activation, which leads to accumulation of miR-199a-5p, which reduces Cav1 expression. Loss of Cav1 impairs translocation and compartmentalization of HO-1 at the plasma membrane (PM); (B) blunted PI3K/AKT signaling in CF cells results in elevated levels of active GSK3β, which leads to Nrf2 ubiquitination and proteasomal degradation and (C) affects the stability of HIF-1α. (D) NF-kB in CF cells competes for the Nrf2 co-activator CBP/p300, thus preventing Nrf2 transcriptional activity.
Figure 4
Figure 4
CO-mediated induction of HO-1. Low dose CO can activate all the transcriptional factors (TFs) that drive the expression of HO-1, via either direct or indirect activation of MKK3/p38 MAPKs and PI3K/AKT signaling.
Figure 5
Figure 5
CO beneficial effects in cystic fibrosis (CF). CO may have several beneficial effects in CF. In addition to transcriptional induction of HO-1, CO helps to rebalance ion transport in bronchial epithelial cells by modulating the activity of BKCa channels, ENaC, and, possibly, CFTR. It has direct bactericidal activity and also primes the macrophages. It thus improves the host defense mechanisms by modulating autophagy, phagocytosis, the inflammasome, and immunometabolic responses. CO reduces cellular oxidative stress and improves cell survival by activating/inducing NO, GSH, NADPH, HO-1, PI3K/AKT, and Nrf2. CO also decreases hyper-inflammation by increasing levels of anti-inflammatory mediators, HO-1 and SPMs.
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