The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient patrolling monocytes into Nr4a1-deficient mice prevented tumor invasion in lung. Patrolling monocytes established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature and promoted natural killer cell recruitment and activation. Thus, patrolling monocytes contribute to cancer immunosurveillance and may be targets for cancer immunotherapy.
Nonclassical patrolling monocytes are characterized by their unique ability to actively patrol the vascular endothelium under homeostatic and inflammatory conditions. Patrolling monocyte subsets (CX3CR1highLy6C− in mouse, and CX3CR1highCD14dimCD16+ in humans) are distinct from the classical monocyte subsets (CCR2highLy6C+ in mouse, and CCR2highCD14+CD16− in humans) and exhibit unique functions in the vasculature and inflammatory disease. Patrolling monocytes function in a number of disease settings to remove damaged cells and debris from the vasculature, and have been associated with wound healing and the resolution of inflammation in damaged tissues. This review highlights the unique functions of these patrolling monocytes in the vasculature and during inflammation.
Impaired T-cell responses in chronic hepatitis C virus (HCV) patients have been reported to be associated with the establishment of HCV persistent infection. However, the mechanism for HCV-mediated T-cell dysfunction is yet to be defined. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in suppressing T-cell responses. In this study we examined the accumulation of MDSCs in human peripheral blood mononuclear cells (PBMCs) following HCV infection. We found that CD33+ mononuclear cells cocultured with HCV-infected hepatocytes, or with HCV core protein, suppress autologous T-cell responses. HCV core-treated CD33+ cells exhibit a CD14+CD11b+/lowHLADR−/low phenotype with up-regulated expression of p47phox, a component of the NOX2 complex critical for reactive oxygen species (ROS) production. In contrast, immunosuppressive factors, arginase-1 and inducible nitric oxide synthase (iNOS), were not up-regulated. Importantly, treatment with an inactivator of ROS reversed the T-cell suppressive function of HCV-induced MDSCs. Lastly, PBMCs of chronic HCV patients mirror CD33+ cells following treatment with HCV core where CD33+ cells are CD14+CD11b+HLADR−/low, and up-regulate the expression of p47phox. Conclusion These results suggest that HCV promotes the accumulation of CD33+ MDSC, resulting in ROS-mediated suppression of T-cell responsiveness. Thus, the accumulation of MDSCs during HCV infection may facilitate and maintain HCV persistent infection.
Molecular mechanisms linking the sympathetic stress response and inflammation remain enigmatic. Here we demonstrate that the transcription factor Nr4a1 regulates production of norepinephrine (NE) in macrophages, thereby limiting experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated leukocyte infiltration to the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected against EAE. Further, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of macrophage catecholamine production.
Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-␥ production have been reported to be associated with persistent HCV infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen-presenting cells (APCs). The activation of STAT proteins has been reported to regulate the inflammatory responses and differentiation of APCs. To further characterize the molecular basis for the regulation of APC function by extracellular HCV core, we examined the ability of extracellular HCV core to activate STAT family members (STAT1, -2, -3, -5, and -6). In this study, we report the activation of STAT3 on human monocytes, macrophages, and dendritic cells following treatment with extracellular HCV core as well as treatment with a gC1qR agonistic monoclonal antibody. Importantly, HCV core-induced STAT3 activation is dependent on the activation of the PI3K/Akt pathway. In addition, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection.
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