Tryptophanyl tRNA Synthetase from Human Macrophages Infected by Porphyromonas gingivalis Induces a Proinflammatory Response Associated with Atherosclerosis

Porphyromonas gingivalis is the most common microorganism associated with adult periodontal disease, causing inflammation around the subgingival lesion. In this study, we investigated tryptophanyl tRNA synthase (WRS) production by THP-1 cells infected with P. gingivalis. Cytokine production, leukocyte adhesion molecules, and low-density lipoprotein receptor (LDLR) expressions in cultured cells were examined. WRS was detected in THP-1 cell culture supernatants stimulated with P. gingivalis from 1 to 24 h, and apparent production was observed after 4 h. No change in WRS mRNA expression was observed from 1 to 6 h in THP-1 cells, whereas its expression was significantly increased 12 h after stimulation with P. gingivalis. Lactate dehydrogenase (LDH) activity was observed from 4 to 24 h. The TNF-α, IL-6, IL-8, and CXCL2 levels of THP-1 cells were upregulated after treatment with recombinant WRS (rWRS) and were significantly reduced when THP-1 cells were treated with C29. The MCP-1, ICAM-1, and VCAM-1 levels in human umbilical vein endothelial cells were upregulated following treatment with rWRS, and TAK242 suppressed these effects. Additionally, unmodified LDLR, macrophage scavenger receptor A, and lectin-like oxidized LDLRs were upregulated in THP-1 cells treated with rWRS. These results suggest that WRS from macrophages infected with P. gingivalis is associated with atherosclerosis.

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild-type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis. Key messages Msr1 expression is upregulated in prion-infected mouse brains at the terminal stage Msr1 deficiency does not affect prion disease progression Msr1 does not play a major role in prion clearance or prion pathogenesis Microglia-mediated phagocytosis and clearance of Aβ and prion may adopt distinct molecular pathways

High-Expressed Macrophage Scavenger Receptor 1 Predicts Severity Clinical Outcome in Transplant Patient in Idiopathic Pulmonary Fibrosis Disease

Background. Lung transplantation has been performed worldwide and admitted as an effective treatment for patients with various end-stage lung diseases. However, limit reliable clinical indicators exist to identify patients at high risk for allograft failure in lung transplant recipients. The recent advances in the knowledge of immunological aspects of the pulmonary diseases, for that innate macrophage activation, are induced by pathogen or pathogen-derived molecules and widely accepted as the critical evidence among the pathogenesis of lung inflammation and fibrosis. This study was aimed at evaluating the clinical significance of CD86- and macrophage scavenger receptor 1- (MSR1-) positive cells during the development of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH), and their potential roles in the prediction of the outcomes after lung transplantation were examined. Methods. Tissues from lung transplantation for 37 IPF and 15 PAH patients from the Department of Cardiothoracic Surgery in Wuxi People’s Hospital from December 2015 to December 2016 were analyzed by immunohistochemistry (IHC) for detecting the expression and CD86 and MSR1 and correlated with clinical events after lung transplantation. Results. IHC results showed that the expression of MSR1, IL-13, and arginase-1 (Arg1) but not CD86 in the lung section of IPF patients was dramatically enhanced when compared with that of PAH patients. The expression of MSR1, IL-13, and Arg1 but not CD86 in the lung from IPF patients with smoking was significantly increased when compared with that from nonsmoking subjects. In addition, the expression of MSR1-positive cells in IPF subjects with Klebsiella pneumoniae infection was dramatically enhanced than that in noninfection subjects. MSR1-positive macrophages were negatively associated with FEV1 and with FVC but not associated with TLC and with TLCO. However, CD86-positive macrophages were not significantly associated with the above lung function-related factors. Furthermore, MSR1 had a higher area under the ROC curve (AUC) than CD86 for IPF diagnosis. Survival analysis indicated that high levels of MSR1-positive macrophages had a worse prognostic effect for IPF patients with lung transplantation. Conclusion. Our study indicates the clinical significance of Klebsiella pneumoniae infection-related MSR1-positive cells in IPF progression, and it could be a prognostic marker in IPF after the lung transplant; development strategies to reduce the expression of MSR1-positive macrophages in IPF may be beneficial for the lung transplant.

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain, and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance, and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis.

Systemic blockade of Clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors

Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell targeting therapies. Thus, agents that can reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Here, we report that immunotherapeutic targeting of the macrophage scavenger receptor Clever-1 in heavily pretreated metastatic cancer patients was able to induce a significant increase and activation of peripheral T-cells. Anti-Clever-1 (FP-1305) administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. Mechanistically, Clever-1 inhibition impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved macrophage cross-presentation of scavenged antigens. Our results reveal a non-redundant role played by the receptor Clever-1 in suppressing adaptive immune cell activation in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch potentially leading to intratumoral proinflammatory responses in metastatic cancer patients.

Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1−/− cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.