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    • An important aspect of macrophage biology highly influenced

    2022-06-10

    An important aspect of macrophage biology, highly influenced by HO-1 activity, is macrophage polarization. The broadest classification, based on the in vitro stimulation, surface marker expression, and inflammatory cytokines production, describes macrophages as classically activated, proinflammatory (M1) and alternatively activated, anti-inflammatory, associated with tissue repair (M2) [34] (Table 1). Unfortunately, such simplification reflects neither the complex in vivo microenvironment nor the real diversity of macrophage populations. Although several types of macrophages were distinguished (including M2 subtypes, hemorrhage-associated, generated with oxidized lipids and M4, Table 1), assignment of these JNJ26481585 sale to a specific subgroup undoubtedly still remains challenging [35,36]. In general, differentiation towards anti-inflammatory phenotype is associated with increased heme catabolism by HO-1 and iron retention by ferritin together with upregulation of CD163 expression [37]. Such properties are also relevant for cardiac resident macrophages [38] and their more detailed characteristics is described below in this review. Importantly, it was demonstrated that polarization towards an M2 phenotype can be achieved through exposure of human macrophages to apoptotic cells and the mechanism involves upregulation of HO-1 by sphingosine-1-phosphate derived from cells undergoing apoptosis [39]. Furthermore, in some experimental models, the M2 phenotype was linked to induction of HO-1 expression in macrophages by hemin and adiponectin (reviewed in: [40]).
    Role of HO activity products in modulation of inflammation At first, HO-1 was regarded as an enzyme pivotal for heme catabolism and iron recirculation. However, throughout the years, HO-1 has also been described as an enzyme exhibiting significant anti-inflammatory, anti-oxidant and cytoprotective properties [41]. These effects derive not only from regulation of heme-iron homeostasis, but are exerted also by heme catabolism end products – CO and biliverdin [[42], [43], [44]]. In 1949, a constant production of carbon monoxide in human was reported. What is more, increased production of CO correlated with the abnormal decomposition of erythrocytes [45]. Almost twenty years later increased CO production was observed in patients suffering from hemolytic anemia [46]. The mystery was finally unraveled when the activity of HO, responsible for generation of CO, was described. CO is a signaling molecule involved in many biological processes. Early studies revealed that CO in some aspects is similar to nitric oxide since it was recognized as a neurotransmitter as well [47]. They both are able to activate soluble guanylyl cyclase (sGC), which subsequently generates cyclic GMP [48]. This results in suppression of apoptosis [44], blood vessel relaxation [49], decreased adhesion of leukocytes [50] and inhibition of platelet aggregation [51]. Although CO is mostly associated with its toxicity related to inhibition of O2 binding to ferrous iron in Hb, such ability to interact with hemoproteins is critical for cell signalling during inflammation [52,53]. Through binding to heme a3 of cytochrome c oxidase in the respiratory chain, it contributes to the reduction of mitochondrial electron transport and therefore increase in ROS production [54] (Fig. 2B). In this case, rapid burst of ROS enables upregulation of peroxisome proliferator-activated receptor γ (PPARγ) – nuclear hormone receptor, which mediates expression of numerous genes involved in immune responses. In macrophages PPARγ downregulates proinflammatory cytokines including TNFα, IL-1β and IL-6 [55] (Fig. 2B). CO may influence the generation of new blood vessels, as it induces biosynthesis of vascular endothelial growth factor, a potent activator of angiogenesis [51,56]. Moreover, CO is also involved in stromal cell-derived factor-1-driven angiogenesis [57] and may stimulate proliferation of endothelial cells (ECs) [58,59]. What is more, CO can modulate mitogen-activated protein kinase (MAPK) signal transduction, as it was shown to affect both p38 MAPK and c-Jun N-terminal kinase (JNK) pathways (Fig. 2B). In macrophages, CO contributed to reduced JNK phosphorylation and thus attenuated IL-6 production [60] (Fig. 2B). Upon LPS stimulation, CO acts through p38 MAPK pathway [61]. It dampens inflammatory signalling due to inhibition of TNFα, IL-1β, macrophage inflammatory protein-1β (MIP-1β) expression and upregulation of anti-inflammatory interleukin-10 (IL-10) [61] (Fig. 2B). This cytokine is a part of the so-called positive feedback loop on HO-1/IL-10 axis. In such situation, CO generated in macrophages by HO-1 promotes IL-10 production while in turn, this interleukin upregulates HO-1 expression through MAPK and signal transducer and activator of transcription 3 (STAT-3) pathways [[61], [62], [63]]. This mechanism allows for significant signal amplification in monocytes/macrophages and consequently resolution of inflammation.