CD4⁺ regulatory T cells (Tregs), accounting for approximately 5–10% of total circulating CD4⁺ T cells, represent a critical subset of T lymphocytes involved in immune homeostasis. Through a broad set of effector mechanisms, these cells contribute to immune tolerance to self-constituents and to mucosal antigens derived from the commensal microflora and food (Lu et al., 2017; Xing and Hogquist, 2012). Tregs also participate in the resolution of inflammatory responses (Dominguez-Villar and Hafler, 2018) and play an important role in maternal immunotolerance against the semi-allogeneic fetus (Samstein et al., 2012). While critical to maintain tissue integrity, excessive activation of Tregs impedes adequate immune responses to tumors and pathogens, suggesting a tight control of their suppressive activity and tissue localization (Togashi et al., 2019; Aandahl et al., 2004; van der Burg et al., 2007). Although uniformly characterized by the expression of the lineage-specific, Foxp3 transcription factor (Lu et al., 2017), regulatory T cells display a wide range of phenotypic and functional properties that allow them to migrate to specific sites and suppress a variety of immune reactions, including inflammatory (Caridade et al., 2013) and humoral responses (Clement et al., 2019). Although diverse, the mechanisms whereby Tregs antagonize the activity of immune effectors are largely paracrine in nature (Vignali et al., 2008). Short-range suppressive mechanisms include competition for nutrients and/or growth factors (mostly cytokines), secretion of immunosuppressive factors, and direct, contact-mediated, inactivation of antigen-presenting cells (Wardell et al., 2021). These findings suggest that Tregs have to adapt to multiple lymphoid and nonlymphoid environments and suppress immune responses in a context and tissue-dependent fashion (Shevyrev and Tereshchenko, 2019; Panduro et al., 2016).

Oxygen represents an essential component of cellular bioenergetics and biochemistry. Because oxygen tension varies according to tissues and pathophysiological states (Ast and Mootha, 2019), cells need to adapt to fluctuations in oxygen availability in order to maintain an adequate functional and metabolic status. Of note, low-oxygen availability (hypoxia) plays a critical role in the pathophysiology of many immune disorders (McKeown, 2014; Bartels et al., 2013). Inflammation, in particular, is thought to reduce oxygen availability to tissues by affecting microvascular form and function, and through the recruitment of highly oxygen-consuming inflammatory cells producing NADPH oxidase-derived reactive oxygen species (Nanduri et al., 2015).

Immune cells patrolling through lymphoid and nonlymphoid tissues need therefore to readily adapt to varying oxygen concentration levels in order to exert their function (Mempel and Marangoni, 2019), suggesting an important role for oxygen sensors in immune regulation. Several hypoxia-sensitive pathways are known to enable single-cell survival in low-oxygen settings. In particular, reduced oxygen levels are directly sensed by a family of oxygen-dependent prolyl hydroxylases (PHD encoded by Egln gene, comprising three members) (Hirota, 2020), although other mechanisms mediated by oxygen-sensitive histone lysine demethylases (KDM) and the cysteamine dioxygenase/N-degron pathway have been recently uncovered (Baik and Jain, 2020). Hypoxia-inducible factors (HIFs), a set of evolutionary conserved transcriptional regulators, represent the best-described substrates of PHDs. These factors are heterodimers composed of a HIFα subunit whose stability is directly controlled by oxygen availability and a constitutively expressed HIF1β subunit (also known as ARNT) (Wang and Semenza, 1995). Following the initial characterization of the first member of HIFα family (HIF1α), two additional members, HIF2α and HIF3α, have been identified and shown to be similarly regulated by O₂ availability and bind to HIF1β (Webb et al., 2009). In normoxia, PHDs, whose affinity for oxygen is low and comparable to atmospheric concentrations, catalyze the prolyl-hydroxylation of HIFα subunits (Semenza, 2001). This post-translational modification allows recognition and ubiquitination of HIFα subunits by the E3 ubiquitin ligase Von Hippel–Lindau protein (pVHL) and subsequent degradation by the proteasome (Maxwell et al., 1999). In hypoxia, nonhydroxylated alpha subunits escape degradation and translocate to the nucleus where they bind to constitutively expressed and stable beta subunits to constitute an active heterodimer able to regulate gene expression. This process promotes transcriptional regulation of numerous genes, ultimately leading to increased oxygen supply (such as angiogenesis) and promotion of anaerobic metabolism (Downes et al., 2018).

Multiple levels of complexity of this major regulatory axis have been recently uncovered. As previously suggested, the presence of several members of the PHD and HIF families suggests specialized functions of PHD-HIF pairs during ontogeny and in selected tissues (Watts and Walmsley, 2019). In particular, while HIF1α appears as ubiquitously expressed in all metazoans, HIF2α represents a late acquisition of vertebrates, displaying a more restricted tissue expression pattern (Talks et al., 2000). Although these factors bind to similar sequence motifs (hypoxia response elements [HREs]) and regulate the expression of a shared set of genes, both HIF1α and HIF2α-specific gene targets have been identified in multiple tissues (Downes et al., 2018; Hu et al., 2007; Bono and Hirota, 2020). Further complexity in this pathway stems from the possible occurrence of additional, non-HIF-related, PHD substrates (Meneses and Wielockx, 2016; Mikhaylova et al., 2008; Chan et al., 2009; Romero-Ruiz et al., 2012; Huo et al., 2012; Xie et al., 2015; Lee et al., 2015b; Guo et al., 2016), a set of findings that however has not been confirmed in more rigorous in vitro settings using well-defined synthetic substrates (Cockman et al., 2019).

Hypoxia plays a dual role in inflammation and in the regulation of immune responses. In most settings, hypoxia promotes inflammation, while in some instances, such as in tumor sites, low oxygen levels generally cause unresponsiveness of immune effectors, thus favoring tumor growth. The often-opposing effects displayed by HIF activation on the activity of immune cells equally match this complexity (Corrado and Fontana, 2020). Previous work has indeed highlighted the important role of the PHD-HIF axis in regulating both innate and adaptive immune effectors (Watts and Walmsley, 2019). The role of HIF1α in regulating T cell activity has been described in many studies and is mainly linked to the capacity of this hypoxia-induced transcription factor to promote glycolysis (for a review, see McGettrick and O’Neill, 2020). Accordingly, HIF1α expression favors the development of highly glycolytic inflammatory Th17 cells, while inhibiting the development of Tregs, which rely mostly on aerobic metabolism (Shi et al., 2011). HIF1α also plays a direct role in Th17 development, through the transcriptional activation of Rorc (Dang et al., 2011). The role of HIF1α in Th1 development appears as more complex and context-dependent. Hypoxia decreases IFN-γ production of Th1-like cells in a HIF1α-dependent fashion (Shehade et al., 2015), while sustained expression of this transcription factor in normoxia (as observed in mice lacking PHDs expression; Clever et al., 2016) leads to an increase in IFN-γ-secreting CD4⁺ T cells. Of note, expression of HIF1α can be upregulated in normoxia both by TCR (Lukashev et al., 2001) and cytokine-initiated signals (Dang et al., 2011), confirming that HIF1α may play a role in Th1 cells development both in hypoxia and normoxia.

The role of hypoxia-induced factors in Treg development and function is presently not fully elucidated. As previously discussed, HIF1α deficiency improves Treg cell development, possibly a consequence of the limited requirement for glycolysis of this cell subset (Shi et al., 2011). However, hypoxia promotes Foxp3 expression in a HIF1α-dependent fashion (Ben-Shoshan et al., 2008) and expression of HIF1α is required for adequate regulatory T cell function (Clambey et al., 2012). Similarly, a recent report has identified HIF2α as an important mediator of Treg function in vivo, further stressing the important role of these hypoxia-induced factors in the control of in vivo inflammatory manifestations (Hsu et al., 2020). In agreement with these conclusions, PHD proteins have also been shown to play a role in the differentiation of peripheral (but not thymic-derived) Tregs (Clever et al., 2016). Expression of these proteins appears to redundantly regulate Th1 vs. iTreg development, mostly by limiting the accumulation of HIF1α. In contrast to this study, a recent publication has highlighted a selective role of the PHD2 isoform in the regulation of Treg function (Yamamoto et al., 2019). ShRNA-mediated knockdown of PHD2 expression in Foxp3-expressing cells (PHD2-KD Tregs) led to a systemic inflammatory syndrome characterized by mononuclear cell infiltration in several organs. PHD2-KD Tregs displayed reduced suppressive capacities both in vitro and in vivo, suggesting an important and intrinsic role of PHD2 in this cell subset. Of interest, loss of HIF2α expression reversed the phenotype of these mice bearing PHD2-KD Tregs, suggesting an important role of the PHD2-HIF2α axis in regulating Treg function.

To better delineate the role of PHD2, HIF1α, and HIF2α in the regulation of Treg development and function, we have generated a set of conditional mouse strains lacking expression of these hypoxia-responsive proteins in Foxp3⁺ cells. Using these tools, we confirm herein that mice in which expression of PHD2 is selectively inactivated in regulatory T cells display a spontaneous inflammatory syndrome characterized by altered immune homeostasis at the steady state and high sensitivity to Th1-type inflammatory diseases. This proinflammatory phenotype was accentuated by the concomitant loss of PHD2 and HIF1α, but almost completely alleviated in mice dually deficient for PHD2 and HIF2α. Transcriptome analysis confirmed a marginal role for HIF1α-dependent enhanced glycolysis in the regulation of Treg function and allowed us to identify STAT1 as a potential target of the PHD2-HIF2α axis in maintaining immune homeostasis and preventing excessive Th1-mediated inflammation.

This study highlights the important role of the prolyl-hydroxylase PHD2 in the regulation of Treg development and function. Deletion of PHD2 in developing Tregs led to the accumulation of the subset of Treg precursor characterized by low expression of Foxp3 at the expenses of the mature Foxp3⁺CD25⁺ Treg population (Figure 2c). PHD2-deficient Tregs were nevertheless found in increased numbers in vivo at steady state (Figure 2a), albeit with an altered phenotype. In particular, the expression of molecules known to be associated with optimal suppressive activity (such as Foxp3, ICOS ,and CD25) (Lu et al., 2017; Fontenot et al., 2003; Redpath et al., 2013) was marginally decreased, while the expression of PD-1, a marker associated with altered functional activity of many immune cells including Tregs (Lowther et al., 2016; Tan et al., 2021), was augmented. Of note, other molecules known to play an important role in Treg function were expressed at optimal levels (cf. CTLA4 and IL-10).

Although we have not specifically addressed the role of PHD2 in thymic vs. peripherally induced Tregs, it is noteworthy that lack of PHD2 expression altered Treg thymic development without any major effect on the generation of iTreg in vitro, suggesting a more pronounced role of PHD2 on thymic vs. peripherally generated Tregs, although this conclusion should be strengthened by additional studies.

Mice selectively lacking PHD2 expression in Treg displayed a proinflammatory phenotype (with early manifestations of gastrointestinal tract inflammation) associated to an elevated hematocrit, enhanced vascular permeability, and an altered homeostatic profile of splenic conventional T cells. In marked contrast to WT Tregs, PHD2-deficient Tregs express relatively high levels of Vegfa transcripts (as established from RNA-seq analysis), a factor known to both increase vascular permeability (Bates, 2010) and induce erythropoietin (Epo) production from perivascular stromal cells in several organs (Greenwald et al., 2019). Alternatively, since the expression of the YFP-Cre allele was found in a minor proportion of CD45-negative cells in all organs examined (see Figure 8—figure supplement 1). PHD2 deletion could result in elevated expression of Epo from a nonhematopoietic source. In any event, analysis of several organs (including spleen, liver, and kidney) from PHD2^ΔTreg mice failed to reveal any increase in Epo mRNA accumulation (our own unpublished observations), and further studies will therefore be required to identify the mechanism underlying the observed hematological alterations in PHD2^ΔTreg mice. Several observations, however, strongly indicate that the major proinflammatory phenotype observed in these mice were due to the specific impairment in Treg function consequent to the loss of PHD2 activity. Despite previous reports describing the stochastic activity of the Foxp3-Cre-YFP allele in non-Tregs leading to the recombination of some, but not all, alleles (Franckaert et al., 2015), we consistently found a control-level expression of PHD2 in all conventional T cell subsets tested (Figure 1—figure supplement 1). Secondly, co-transfer of highly purified Tregs with WT naive CD4⁺ conventional target cells clearly demonstrated an intrinsic role of PHD2 in regulating Treg function. Finally, and this will be discussed further below, mice bearing double PHD2-HIF2α-deficient Tregs recover a near-control phenotype, further excluding a major influence of the genetic background on the observed phenotype. Our observations confirm and further extend the observations from a study published during the completion of our work (Yamamoto et al., 2019), indicating a specific nonredundant role for PHD2 in controlling Treg activity in vivo.

Based on the notion that hypoxia-induced factors represent major substrates of PHD2, we generated a series of mouse strains to evaluate the relative role of HIF1α and HIF2α in regulating Treg phenotype and function. The combined loss of PHD2 and HIF2α, but not HIF1α, corrected some, but not all, abnormalities found in the PHD2^ΔTreg mouse strain. To uncover the mechanism whereby the PHD2-HIF2α axis regulates the capacity of Tregs to exert a homeostatic control over conventional T cells, a large transcriptomic analysis was undertaken. To be able to isolate genes specifically involved in the control of Treg activity in naive animals, we took advantage of the graded proinflammatory status of the mouse strain generated (based on colon length and spontaneous activation of Tconv cells, see Figure 6) to identify the gene clusters whose expression correlated with Treg-mediated immune homeostasis. This analysis led us to identify the important pathways providing mechanistic insights into the role of the PHD2-HIF2α axis in Treg biology. In particular, loss of PHD2 led to an altered expression of genes coding for chemokine receptors and adhesion molecules, suggesting a potential role of this oxygen sensor in chemotaxis and traffic. This conclusion is of particular interest in light of two observations described in this study. As previously discussed, PHD2^ΔTreg mice displayed a selective expansion of Th1-prone effectors in all lymphoid organs examined (Figure 1). Accordingly, ubiquitous loss of IFN-γ expression strongly attenuated the pro-inflammatory phenotype of mice with PHD2-deficient Tregs (Figure 5—figure supplement 2), thus suggesting a specific role for PHD2 in endowing Tregs to control Th1-like immune responses in vivo. Secondly, the IPA conducted on the transcriptomic data led to the identification of STAT1 as a potential common regulator of many genes whose expression was under the control of the PHD2-HIF2α axis, including in particular CXCR3 (Hall et al., 2012; Koch et al., 2009). Based on the well-described role for Treg-expressed CXCR3 in modulating Th1-like responses in vivo (Levine et al., 2017; Littringer et al., 2018) and the reduced expression of this chemokine receptor described in this study (Figure 8e), it is tempting to speculate that the reduced capacity of PHD2-deficient Tregs to control Th1 responses is a consequence of an altered STAT1 signaling pathway, leading to reduced CXCR3 expression. It is noteworthy that response to CXCR3 ligands has been recently shown to determine the precise positioning of effector and memory CD8 cells in peripheral lymph nodes (Duckworth et al., 2021). Further studies would be required to identify the precise mechanism at work since the expression of many potential chemokine receptors (including CXCR4, known to exert inhibitory function over other chemokine receptors; Biasci et al., 2020) and adhesion molecules (such as Ly6a or CD44) appears under the control of the PHD2-HIF2α axis in Tregs. Whether altered positioning of Tregs within lymphoid organs represents an important factor contributing to the proinflammatory phenotype of PHD2^ΔTreg mice remains, however, to be thoroughly examined. Similarly, the potential mechanistic link between HIF2α and STAT1 activation remains to be firmly established by further investigations.

Collectively, the observations reported in this study demonstrate a nonredundant role for PHD2 in controlling survival, phenotype, and the capacity of Tregs to control Th1-like responses. These biological responses appear under the control of HIF2α and are largely independent of HIF1α-regulated metabolic pathways. Although the role of the PHD2-HIF2α axis has been previously highlighted by Yamamoto and colleagues using an alternative shRNA-based approach (Yamamoto et al., 2019), our observations do not fully concur with the previous study on two grounds. First, in contrast to PHD2 knockdown (PHD2-KD) cells, PHD2-genetically deficient Tregs retained full suppressive capacities in vitro. Secondly, no sign of reversal to an effector state was found in PHD2-KO regulatory T cells, whereas downregulation of PHD2 expression led to an increased expression of T-bet, GATA-3, and TNFα. Notably, PHD2-KD Tregs were able to induce skin-graft rejection in the absence of bona fide effector cells, suggesting a possible acquisition of effector function by these cells. Although these observations are compatible with a possible gene-dosage effect of PHD2 on Treg biology, further studies are needed to identify the mechanism at work in these two experimental models.

In any events, both studies concur in identifying a possible deleterious role of HIF2α overactivation in the control of regulatory T cell function. These findings appear at odds with a recent publication by Tzu-Sheng Hsu and colleagues in which deletion of HIF2α, but not HIF1α, expression was found to negatively affect Treg function (Hsu et al., 2020). Of note, concomitant deletion of both HIF1α and HIF2α restored the suppressive activity of Tregs (Hsu et al., 2020). An elegant hypothesis, put forward by these authors, may help reconcile some of these apparently contradictory observations. Most experimental evidence concurs with a dual role of HIF1α in Treg differentiation and stability. In the setting of suboptimal Treg-inducing conditions, HIF1α may promote adequate expression of Foxp3 by differentiating Tregs. Once the Treg phenotype has been fully acquired, HIF1α protein expression is reduced following interaction with Foxp3 (Clambey et al., 2012), thus explaining the relative lack of influence of HIF1α on differentiated Tregs. As a consequence, HIF1α-KO Tregs retain full suppressive activity (Hsu et al., 2020). The interaction between HIF1α and Foxp3 can, however, also lead to Foxp3 protein degradation, and thus Treg instability. Therefore, forced stabilization of HIF1α (such as observed in triple PHD KOs [Clever et al., 2016] or pVHL-deficient Tregs [Lee et al., 2015a]) leads to loss of Foxp3 expression and Treg identity and acquisition of proinflammatory functions. Inflammation observed in these mouse strains can be largely attributed to the proinflammatory influence of ex-Tregs. As discussed for HIF1α, HIF2α also appears to regulate Treg stability, albeit in a different direction. Despite a normal phenotype at rest, mice displaying HIF2α-deficient Tregs were largely defective in suppressing inflammation in the gut and lungs (Hsu et al., 2020). This proinflammatory phenotype was largely explained by the HIF1α-dependent reprogramming of HIF2α-deficient Tregs into IL-17-secreting cells. Collectively, the available literature points to a central role for HIF1α in determining Treg stability and function in vivo. Depending on the biological pathway leading to its increased expression and/or protein stabilization, HIF1α promotes the differentiation of Tregs into IFN-γ (in triple PHD KOs or pVHL-deficient Tregs) or IL-17 (in HIF2α-deficient Tregs) secreting cells. Although the mechanism underlying the acquisition of Th1 vs. Th17-like profiles in these models remains to be established, the induction of a glycolytic metabolism is probably instrumental in mediating Treg instability (Shi and Chi, 2019).

In the present study, loss of HIF1α expression did not revert the phenotype of PHD2-HIF2α-deficient Tregs, despite re-establishing a control-like expression of pro-glycolytic genes (Figure 7e). Accordingly, PHD2-deficient Tregs did not acquire the capacity to produce proinflammatory cytokines (Figure 1—figure supplement 1) nor displayed any significant loss of Foxp3 expression upon in vitro culture (Figure 2k and l) or in vivo transfer (Figure 4e). Thus, the available evidence suggests that in PHD2-sufficient cells HIF2α allows adequate Treg function by negating the influence of HIF1α on Foxp3-expression, while overactivation of HIF2α activity secondary to the loss of PHD2 expression leads to altered Treg phenotype, most probably via a STAT1-dependent pathway.

Considering the specific role of PHD2, it is worth mentioning that both the transcriptomic data and our own unpublished observations (indicating an increased sensitivity of triple PHD2-HIF1α-HIF2α Tregs-specific KO mice to chemical induced colitis) suggest that while the capacity of Tregs to control tissue homeostasis in the naive state is under the predominant control of the PHD2-HIF2α axis, other non-HIF PHD2-substrates (Meneses and Wielockx, 2016; Mikhaylova et al., 2008; Chan et al., 2009; Romero-Ruiz et al., 2012; Huo et al., 2012; Xie et al., 2015; Lee et al., 2015b; Guo et al., 2016) probably play an important role in Treg biology under strong inflammatory settings. Finally, this study suggests that some caution should be exerted in the administration of PHD inhibitors presently considered for the treatment of renal anemia (Gupta and Wish, 2017), inflammatory bowel diseases (Marks et al., 2015), as well as Parkinson’s disease (Li et al., 2018) as these compounds may display some proinflammatory effects via the alteration of Treg phenotype and function in vivo.

Sequencing data have been deposited in GEO under accession code GSE184581. Numerical data used to generate the figures have been provided as source data files.

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Author details

1. Yousra Ajouaou

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1734-6505

2. Abdulkader Azouz

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Data curation, Formal analysis, Software, Visualization, Writing - review and editing

   Competing interests

   No competing interests declared

3. Anaëlle Taquin

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Investigation, Methodology, She performed additional experiments and contributed to data analysis, She performed additional experiments and contributed to data analysis

   Competing interests

   No competing interests declared

4. Sebastien Denanglaire

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Hind Hussein

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Methodology, She performed additional experiments and contributed to data analysis, She performed additional experiments and contributed to data analysis

   Competing interests

   No competing interests declared

6. Mohammad Krayem

   1. Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
   2. Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Fabienne Andris

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8644-1020

8. Muriel Moser

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Funding acquisition, Project administration, Resources, Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

9. Stanislas Goriely

   1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
   2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium
   3. Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Charleroi, Belgium

   Contribution

   Project administration, Resources, Writing - review and editing

   Competing interests

   No competing interests declared

10. Oberdan Leo

    1. U-CRI (ULB Center for Research in Immunology), Université Libre de Bruxelles (ULB), Charleroi, Belgium
    2. Immunobiology Laboratory, Université Libre de Bruxelles (ULB), Charleroi, Belgium

    Contribution

    Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing - original draft, Writing - review and editing

    For correspondence

    oberdan.leo@ulb.be

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3621-4743

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