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  • br Methods br Involvement of HO in rheumatic diseases br


    Involvement of HO-1 in rheumatic diseases
    Therapeutic strategy targeted HO-1 Based on the researches focusing on the effect of HO-1 in rheumatic diseases, amount of approaches targeting regulation of HO-1 have been arising (See Table 1 for summary). It has been shown that different strategies such as gene therapy, pharmacologic modulation of HO-1 or administration of metabolic products of HO-1 can display salutary cytoprotective and immunoregulatory effects [6,59]. Many pharmacological compounds, for instance, resveratrol, polyphenols, carnosol and curcumin, which are targeting up-regulation of HO-1 has shown specific anti-inflammatory and antioxidant effects in rheumatic diseases including SLE, arthritis and psoriasis [[60], [61], [62]]. Moreover, administration of CO, which is a main product of HO-1, also displays beneficial effects in rheumatic diseases treatment [63,64]. Currently, the major strategies modulating expression of HO-1 mainly consist of chemical induction and molecular biology technique. The chemical substances, hemin, NO, Simvastatin and metalloporphyrin are generally used for regulating HO-1 expression. With regard to molecular biology technology, siRNA or gene knock-out is the most commonly used method, which can furthest limit the expression of HO-1. On the other hand, transfection of HO-1 vector or Bach1 knock-out can lead to HO-1 overexpression.
    Conclusions and perspectives HO-1 has been identified as an important factor with respect to a number of physiologic systems because of its characteristic anti-inflammatory and anti-oxidative role. Due to the different expressions and various functions of HO-1 in disparate two types of active transport and tissues, there are still many confused and intricate mechanisms about how HO-1 function in related disorders. The salutary antioxidant and anti-inflammatory effects of HO-1 appear to be critically dependent on its concentration and intensity, and inappropriate activation of HO-1 may result in undesirable immunosupression [77]. So it is essential to monitor the HO-1 expression during different phases of the disorders, and levels of HO-1 in different tissues and organs should be further confirmed in order to correlate it with clinical symptoms and other hallmarks of rheumatic diseases. Remarkably, some studies indicate that the enzymatic action of HO-1 is not always related to beneficial effects. For instance, iron, which is released by HO-1 activity, may contribute to lipid peroxidation and even tissue damage [78,79]. Besides, induction of HO-1 by hypoxia/re‑oxygenation and resulting activation of CO/cGMP pathway make a difference to stimulus for macrophage activation, synthesis and release of pro-inflammatory cytokines [80]. HO-1 inhibition also exerts antioxidant effects in some experimental models, such as SJL mice with experimental allergic encephalomyelitis and rat adjuvant arthritis [75,79]. Nevertheless, recent studies suggest the importance of HO-1 goes beyond its enzymatic activity [81]. Particularly, the immunoreactive forms of HO-1 in the nucleus which lack catalytic activity have been proposed to contribute to transcriptional regulation.
    Conflicts of interest
    Acknowledgments This work was supported by the “Personalized Medicines—Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences (grant number: XDA12020107); and the National Basic Research Program of China (973 Program) (grant number: 2014CB541906).
    Introduction Macrophages are an integral part of the mononuclear phagocyte system, which also encompasses monocytes, dendritic cells and osteoclasts [1]. Mononuclear phagocytes share the common function of phagocytosis, but serve distinct roles in different microenvironments and conditions. Macrophages are a highly heterogeneous cell population and their regulatory functions are directed by distinct factors such as tissue localization [2]. For example, stromal macrophages in the bone marrow support erythrocyte differentiation, whereas macrophages in the brain (microglia) promote neurogenesis. Extensive reviews on tissue-specific functions of macrophages have been given by others [1], [2], [3]. Along with its tissue-specific functions, macrophages are principal regulators of immune homeostasis. They can either promote inflammation (M1-polarized macrophages) via a Th1 response by production of pro-inflammatory cytokines and reactive oxygen species (ROS) or inhibit inflammation (M2-polarized macrophages) via a Th2 response by production of anti-inflammatory cytokines [1], [2], [3]. Although the M1/M2 concept has been coined to distinguish various immunologically functional states of macrophages, which is defined by the expression of specific marker subsets, the situation in vivo is much more complex and only incompletely reflected by this categorization. For example, in many pathological conditions macrophages express mixed phenotypes or unique features that cannot be explained with the classical concept of M1/M2 polarization. Importantly, macrophages exhibit high plasticity and can adapt to various local needs and conditions that result in specific phenotypes and subsets [3], [4] to ultimately restore homeostasis after inflammation. In various experimental animal models of inflammatory diseases, fine-tuning of the phenotypical characteristics in macrophages has been shown to promote resolution of inflammation [5], [6]. Heme oxygenase (HO)-1 belongs to the multitude of anti-inflammatory genes expressed by macrophages, whose primary function is to provide heme homeostasis and to protect against free heme-induced toxicity [7]. Interestingly, HO-1 induction in macrophages has been shown to functionally switch these cells to an anti-inflammatory phenotype [8]. In this review, we cover the functional role of macrophage-specific HO-1 in physiology and pathophysiology with a particular focus on the complex interactions with its substrate heme. Moreover, we discuss the possibilities of HO-1-mediated therapeutic strategies to fine-tune macrophage response in inflammatory disorders.