Recently IL was also identified as

Recently, IL-10 was also identified as an important mediator of collagen deposition in the development of HF [64,65]. It was shown, that this cytokine activates macrophages found in the hearts of mice suffering from diastolic dysfunction in the autocrine manner [64]. In response, specific subset of macrophages increases production of osteopontin, which acts as a paracrine fibroblast activator. Upon such stimulation, cardiac fibroblasts become activated and promote collagen deposition. This leads to myocardial stiffness and HF. Additionally, IL-10 acting directly on macrophages enhances their phagocytic ability [65]. Altogether, IL-10 can contribute to tissue repair by promoting fibrosis and clearance of apoptotic cells. Yet, the significance of HO-1 in IL-10-mediated actions of macrophages remains to be elucidated. Biliverdin, another product of HO activity is rapidly converted to bilirubin by BvR (Fig. 1). Primarily, biliverdin and bilirubin were considered as heme degradation waste products, however, these bile pigments possess compelling antioxidative and anti-inflammatory properties [42]. They protect proteins and lipids from peroxidation. Bilirubin acts as a singlet oxygen, superoxide anion or hydroxyl radical scavenger and this action is associated with recovery of biliverdin [66] (Fig. 1). Apart from very potent antioxidative properties, it plays an important role in inhibition of complement activation and T-cell proliferation [[67], [68], [69]]. It also decreases P- and E-selectin expression on ECs which results in attenuation of leukocyte rolling [70]. Biliverdin contributes to downregulation of TLR4 expression in macrophages (Fig. 2B) via direct binding of BvR to TLR4 promoter [71]. Additionally, biliverdin is sensed by aryl hydrocarbon receptor (AhR), which is a transcription factor mediating macrophage activation [72,73] (Fig. 2B). AhR nuclear translocation is induced by binding of tryptophan metabolism products generated by heme-containing dioxygenases: indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase [74]. Thus, the activity of these orexins may be affected by another HO activity product – CO, which can bind to heme ferrous iron [53]. On the other hand, heme degradation per se decreases its availability for the synthesis of hemoproteins and possibly impair their maturation [43]. Such effect was demonstrated for cyclooxygenase-2 (COX2) and nitric oxide synthase (NOS), as after HO-1-induced heme depletion their expression and activity are reduced [75,76] (Fig. 2B). Another important example is NAD(P)H oxidase (NOX), an enzyme crucial for macrophage effector functions. NOX is responsible for superoxide anion production which, apart from its classical role in killing pathogens, is involved in regulation of expression of redox-sensitive genes [77]. Since heme is a component of gp91phox NOX subunit, restriction of its availability by HO-1 may influence not only ROS generation but also downstream signalling pathways [78]. Indeed, recently it was demonstrated that in circulating monocytes HO-1 expression negatively correlates with ROS formation in the aortas of mice, as well as with expression and activity of NOX2 [79]. While heme degradation products have a very broad range of immunomodulatory properties, HO-1 protein itself may interfere with TLR3 and TLR4 signalling. For these TLRs, transduction of signal involves TIR domain-containing adaptor-inducing interferon β (TRIF) and interferon regulatory factor 3 (IRF3). It was demonstrated that in HO-1-deficient macrophages IRF3 nuclear accumulation was reduced affecting IRF3 target genes expression such as interferon β, RANTES, interferon gamma-induced protein 10 (IP-10) and monocyte chemoattractant protein 1 (MCP-1) and suggesting a direct interaction between HO-1 and IRF-3 [80]. In fact, HO is anchored in the endoplasmic reticulum (ER) with its hydrophobic C-terminus, facing the cytosol [81]. Oxidative stress, such as hypoxia, leads to signal peptide peptidase (SPP)-mediated intermembrane cleavage of HO-1 at the C-terminus and its release to the cytosol [82]. Truncated HO-1 loses its enzymatic activity and may be translocated to the nucleus and act as a modulator of transcription factors [83]. Interestingly, as HO-1 is not a traditional transcription factor with DNA binding motifs, rather an indirect transcriptional activation is more likely to occur [84].