Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, is a type I single transmembrane protein mainly expressed in myeloid cells, such as monocytes, macrophages, glial cells, and osteoclasts. The endogenous ligands, colony-stimulating factor-1 (CSF-1) and Interleukin-34 (IL-34), activate CSF-1R and downstream signaling pathways including PI3K-AKT, JAK-STATs, and MAPKs, and modulate the proliferation, differentiation, migration, and activation of target immune cells. Over the past decades, the promising therapeutic potential of CSF-1R signaling inhibition has been widely studied for decreasing immune suppression and escape in tumors, owing to depletion and reprogramming of tumor-associated macrophages. In addition, the excessive activation of CSF-1R in inflammatory diseases is consecutively uncovered in recent years, which may result in inflammation in bone, kidney, lung, liver and central nervous system. Agents against CSF-1R signaling have been increasingly investigated in preclinical or clinical studies for inflammatory diseases treatment. However, the pathological mechanism of CSF-1R in inflammation is indistinct and whether CSF-1R signaling can be identified as biomarkers remains controversial. With the background information aforementioned, this review focus on the dialectical roles of CSF-1R and its ligands in regulating innate immune cells and highlights various therapeutic implications of blocking CSF-1R signaling in inflammatory diseases. 

Targeting CSF-1R represents an effective strategy in modulating inflammatory diseases.

The article describes how atherosclerosis and coronavirus disease 19 (COVID-19) may affect each other. The features of this comorbid pathogenesis at various levels (vascular, cellular and molecular) are considered. A bidirectional influence of these conditions is described: the presence of cardiovascular diseases affects different individuals’ susceptibility to viral infection. In turn, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can have a negative effect on the endothelium and cardiomyocytes, causing blood clotting, secretion of pro-inflammatory cytokines, and thus exacerbating the development of atherosclerosis. In addition to the established entry into cells via angiotensin-converting enzyme 2 (ACE2), other mechanisms of SARS-CoV-2 entry are currently under investigation, for example, through CD147. Pathogenesis of comorbidity can be determined by the influence of the virus on various links which are meaningful for atherogenesis: generation of oxidized forms of low-density lipoproteins (LDL), launch of a cytokine storm, damage to the endothelial glycocalyx, and mitochondrial injury. The transformation of a stable plaque into an unstable one plays an important role in the pathogenesis of atherosclerosis complications and can be triggered by COVID-19. The impact of SARS-CoV-2 on large vessels such as the aorta is more complex than previously thought considering its impact on vasa vasorum. Current information on the mutual influence of the medicines used in the treatment of atherosclerosis and acute COVID-19 is briefly summarized.

/pdf/atherosclerosis-cardiovascular-disorders-and-covid-19-2visewab.pdf

Atherosclerosis, Cardiovascular Disorders and COVID-19: Comorbid Pathogenesis

Objective Immune changes play fundamental roles in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). Previous studies have revealed alterations in immune responses of patients with non-severe and severe COVID-19. Therefore, this study investigated whether interleukin-27 (IL-27) and interleukin-32 (IL-32) levels may be considered as predicting factors for determining the severity and outcome of COVID-19. Methods The blood samples were collected from 50 non-severe and severe patients infected with COVID-19 and 25 healthy subjects. The serum samples were isolated from the whole blood. The levels of IL-27 and IL-32 were measured by enzyme-linked immunosorbent assay and percentages of some immune cells were studied by cell counter. Results The levels of IL-27 and IL-32 were significantly higher in COVID-19 patients than healthy subjects (p < 0.0001–0.01). IL-27 was significantly reduced in severe COVID-19 patients who needed to undergo ICU therapy (p < 0.05). Disease severity was significantly associated with IL-27 level in patients with COVID-19 (p < 0.05), unlike IL-32 level. There was a significant association between IL-27 and IL-32 in participants (p < 0.0001, odds ratio (OR) = 0.9873; 95% confidence interval (CI) = 0.9998 to 1.000; p < 0.05, OR = 0.4462; 95% CI = 0.08,579 to 0.7802; p < 0.01, OR = 0.6640, 95% CI = 0.3007–0.8590). IL-27 level was significantly higher in the recovered subjects than dead cases (p < 0.0001). IL-27 and IL-32 levels in patients who had fever were significantly higher than those who did not have (p < 0.01–0.05), unlike patients who suffered from cough (p < 0.001–0.01). The IL-27 level in patients with non-severe COVID-19 was directly correlated with CRP value (p < 0.05, OR = 0.5,722,357, 95% CI = 0.06,807,176–0.8,435,928). IL-27 and IL-32 levels in non-severe patients were positively associated with NLR (p < 0.01, OR = 0.7292; 95% CI = 0.2809 to 0.9163; p < 0.01, OR = 0.6537, 95% CI = 0.1425–0.8896). Patients with severe COVID-19 had a significant increase in NLR (p < 0.0001–0.05). NLR was significantly correlated with the disease severity (p < 0.0001–0.05). Survivors had a significant reduction in NLR compared with those who succumbed to COVID-19 (p < 0.05). Conclusion Change in IL-27 level along with the frequencies of some immune cells may serve as a predictor of the severity and outcome of COVID-19.

Predicting roles of IL-27 and IL-32 in determining the severity and outcome of COVID-19

IL-37 is a newly discovered inflammatory factor. However, the protective effect and underlying mechanisms of IL-37 on atherosclerosis remain unclear. In the present study, IL-37 was used for intraperitoneal injection in diabetic ApoE-/- mice caused by streptozotocin. High glucose (HG)/ox-LDL was used to stimulate THP-1 original macrophage followed by IL-37 pretreatment in vitro. The atheromatous plaque area, oxidative stress and inflammation levels in ApoE-/- mice were evaluated, and the level of macrophage ferroptosis was detected in vivo and in vitro. It was identified that IL-37 treatment significantly decreased plaque area in diabetic ApoE-/- mice. IL-37 not only improved blood lipid levels in mice, but also reduced serum levels of inflammatory factors including IL-1β and IL-18. Furthermore, IL-37 increased GPX4 and nuclear factor erythroid 2-related factor 2 (NRF2) in the aorta of diabetic mice. In vitro experiment revealed that IL-37 inhibited HG/ox-LDL-induced ferroptosis in macrophages, as evidenced by improved cell membrane oxidation, reduced malondialdehyde production and increased GPX4 expression. Moreover, it was also found that IL-37 enhanced the nuclear translocation of NRF2 in macrophages, while ML385, a specific NRF2 inhibitor, significantly attenuated the protective effect of IL-37 on macrophage ferroptosis caused by HG/ox-LDL. In conclusion, IL-37 suppressed macrophage ferroptosis to attenuate atherosclerosis progression via activating the NRF2 pathway.

/pdf/il-37-suppresses-macrophage-ferroptosis-to-attenuate-1153n1v5.pdf

IL‑37 suppresses macrophage ferroptosis to attenuate diabetic atherosclerosis via the NRF2 pathway

Interleukin-37 (IL-37) is a newly discovered member of IL-1 family. The cytokine was proved to have extensive protective effects in infectious diseases, allergic diseases, metabolic diseases, autoimmune diseases and tumors since its discovery. IL-37 was mainly produced by immune and some non-immune cells in response to inflammatory stimulus. The IL-37 precursors can convert into the mature forms after caspase-1 cleavage and activation intracellularly, and then bind to Smad-3 and transfer to the nucleus to inhibit the production and functions of proinflammatory cytokines; extracellularly, IL-37 binds to cell surface receptors to form IL-37/IL-18Rα/IL-1R8 complex to exert immunosuppressive function via inhibiting/activating multiple signal pathways. In addition, IL-37 can attenuate the pro-inflammatory effect of IL-18 through directly or forming an IL-37/IL-18BP/IL-18Rβ complex. Therefore, IL-37 has the ability to suppress innate and acquired immunity of the host, and effectively control inflammatory stimulation, which was considered as a new hallmark of cancer. Specifically, it is concluded that IL-37 can inhibit the growth and migration of tumor cells, prohibit angiogenesis and mediate the immunoregulation in tumor microenvironment, so as to exert effective anti-tumor effects. Importantly, latest studies also showed that IL-37 may be a novel therapeutic target for cancer monitoring. In this review, we summarize the immunoregulation roles and mechanisms of IL-37 in anti-tumor process, and discuss its progress so far and potential as tumor immunotherapy.

Novel insights into IL-37: an anti-inflammatory cytokine with emerging roles in anti-cancer process

Atherosclerosis, which is a primary cause of cardiovascular disease (CVD) deaths around the world, is a chronic inflammatory disease that is characterised by the accumulation of lipid plaques in the arterial wall, triggering inflammation that is regulated by cytokines/chemokines that mediate innate and adaptive immunity. This review focuses on IL-32, -34 and -37 in the stable vs. unstable plaques from atherosclerotic patients. Dysregulation of the novel cytokines IL-32, -34 and -37 has been discovered in atherosclerotic plaques. IL-32 and -34 are pro-atherogenic and associated with an unstable plaque phenotype; whereas IL-37 is anti-atherogenic and maintains plaque stability. It is speculated that these cytokines may contribute to the explanation for the increased occurrence of atherosclerotic plaque rupture seen in patients with COVID-19 infection. Understanding the roles of these cytokines in atherogenesis may provide future therapeutic perspectives, both in the management of unstable plaque and acute coronary syndrome, and may contribute to our understanding of the COVID-19 cytokine storm.

/pdf/clinical-implications-of-il-32-il-34-and-il-37-in-kmq48837an.pdf

Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19

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Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19