Myeloid-derived suppressor cells (MDSCs) hinder antitumor immunity in multiple cancer types. While brequinar (BRQ), an inhibitor of dihydroorotate dehydrogenase, shows cytotoxicity in hematological ...malignancy, it has not yet been adapted to attenuate MDSCs by augmenting bone marrow progenitors in breast cancer. In this issue of the JCI, Colligan et al. demonstrate that BRQ restored terminal differentiation of MDSCs. Using in vivo models of immunotherapy-resistant breast cancer, the authors uncovered a mechanism by which BRQ promoted myeloid cell differentiation by limiting their suppressive function and enhancing the efficacy of immune checkpoint blockade therapy. The findings offer insight into the biogenesis of MDSCs, provide an alternative avenue for cancers that remain unresponsive to conventional therapies, and may be extended to future translational studies in patients.
Pathogenesis induced by SARS-CoV-2 is thought to result from both an inflammation-dominated cytokine response and virus-induced cell perturbation causing cell death. Here, we employ an integrative ...imaging analysis to determine morphological organelle alterations induced in SARS-CoV-2-infected human lung epithelial cells. We report 3D electron microscopy reconstructions of whole cells and subcellular compartments, revealing extensive fragmentation of the Golgi apparatus, alteration of the mitochondrial network and recruitment of peroxisomes to viral replication organelles formed by clusters of double-membrane vesicles (DMVs). These are tethered to the endoplasmic reticulum, providing insights into DMV biogenesis and spatial coordination of SARS-CoV-2 replication. Live cell imaging combined with an infection sensor reveals profound remodeling of cytoskeleton elements. Pharmacological inhibition of their dynamics suppresses SARS-CoV-2 replication. We thus report insights into virus-induced cytopathic effects and provide alongside a comprehensive publicly available repository of 3D datasets of SARS-CoV-2-infected cells for download and smooth online visualization.
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•Integrative imaging approaches reveal SARS-CoV-2-induced cellular alterations•SARS-CoV-2 extensively remodels the cellular endomembrane system•Pharmacological inhibition of cytoskeleton remodeling restricts viral replication•We provide a comprehensive repository of virus-induced ultrastructural cell changes
Cortese et al. use integrative imaging techniques to generate a publicly available repository of morphological alterations induced by SARS-CoV-2 in lung cells. Accumulation of ER-derived double-membrane vesicles, the viral replication organelle, occurs concomitantly with cytoskeleton remodeling and Golgi fragmentation. Pharmacological alteration of cytoskeleton dynamics restricts viral replication and spread.
The Macrophage Iron Signature in Health and Disease Mertens, Christina; Marques, Oriana; Horvat, Natalie K. ...
International journal of molecular sciences,
08/2021, Letnik:
22, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote ...homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
Background and Aims
TGFβ/bone morphogenetic protein (BMP) signaling in the liver plays a critical role in liver disease. Growth factors, such as BMP2, BMP6, and TGFβ1, are released from LSECs and ...signal in a paracrine manner to hepatocytes and hepatic stellate cells to control systemic iron homeostasis and fibrotic processes, respectively. The misregulation of the TGFβ/BMP pathway affects expression of the iron‐regulated hormone hepcidin, causing frequent iron overload and deficiency diseases. However, whether LSEC‐secreted factors can act in an autocrine manner to maintain liver homeostasis has not been addressed so far.
Approach and Results
We analyzed publicly available RNA‐sequencing data of mouse LSECs for ligand‐receptor interactions and identified members of the TGFβ family (BMP2, BMP6, and TGFβ1) as ligands with the highest expression levels in LSECs that may signal in an autocrine manner. We next tested the soluble factors identified through in silico analysis in optimized murine LSEC primary cultures and mice. Exposure of murine LSEC primary cultures to these ligands shows that autocrine responses to BMP2 and BMP6 are blocked despite high expression levels of the required receptor complexes partially involving the inhibitor FK‐506–binding protein 12. By contrast, LSECs respond efficiently to TGFβ1 treatment, which causes reduced expression of BMP2 through activation of activin receptor‐like kinase 5.
Conclusions
These findings reveal that TGFβ1 signaling is functionally interlinked with BMP signaling in LSECs, suggesting druggable targets for the treatment of iron overload diseases associated with deficiency of the BMP2‐regulated hormone hepcidin, such as hereditary hemochromatosis, β‐thalassemia, and chronic liver diseases.
Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive ...tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. ...Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.
The respiratory tract is constantly exposed to pathogens that require iron for proliferation and virulence. Pulmonary iron levels are increased in several lung diseases and associated with increased ...susceptibility to infections. However, regulation of lung iron homeostasis and its cross talk to pulmonary immune responses are largely unexplored. Here we investigated how increased lung iron levels affect the early pulmonary inflammatory response. We induced acute local pulmonary inflammation via aerosolized LPS in a mouse model of hereditary hemochromatosis type 4 (
), which is hallmarked by systemic and pulmonary iron accumulation, specifically in alveolar macrophages. We show that
mice display a mild attenuation in the LPS-induced pulmonary inflammatory response, with a reduced upregulation of some pro-inflammatory cytokines and chemokines. Despite mildly reduced cytokine levels, there is no short-term impairment in the recruitment of neutrophils into the bronchoalveolar space. These data suggest that increased pulmonary iron levels do not strongly alter the acute inflammatory response of the lung.
Iron is an essential co‐factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to ...macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine‐block‐poly(S‐ethylsulfonyl‐l‐cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S‐ethylsulfonyl‐l‐cysteine) block, yielding glutathione‐responsive core cross‐linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild‐type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox‐responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.
Delivery of iron to macrophages triggers sterile inflammation. To provide stable encapsulation in human blood plasma yet triggered release inside cells, superparamagnetic iron oxide nanoparticles (SPIONs) are surface‐functionalized and embedded in core cross‐linked micelles derived of polypept(o)ides. Stimulated uptake and degradation by macrophages induce strong inflammatory responses establishing SPION‐core cross‐linked polymeric micelles an immunostimulatory agent to counteract undesired immune tolerance.
Myeloid-derived suppressor cells (MDSCs) hinder antitumor immunity in multiple cancer types. While brequinar (BRQ), an inhibitor of dihydroorotate dehydrogenase, shows cytotoxicity in hematological ...malignancy, it has not yet been adapted to attenuate MDSCs by augmenting bone marrow progenitors in breast cancer. In this issue of the JCI, Colligan et al. demonstrate that BRQ restored terminal differentiation of MDSCs. Using in vivo models of immunotherapy-resistant breast cancer, the authors uncovered a mechanism by which BRQ promoted myeloid cell differentiation by limiting their suppressive function and enhancing the efficacy of immune checkpoint blockade therapy. The findings offer insight into the biogenesis of MDSCs, provide an alternative avenue for cancers that remain unresponsive to conventional therapies, and may be extended to future translational studies in patients.
Myeloid-derived suppressor cells (MDSCs) hinder antitumor Immunity In multiple cancer types. While brequinar (BRQ), an inhibitor of dihydroorotate dehydrogenase, shows cytotoxicity in hematological ...malignancy, it has not yet been adapted to attenuate MDSCs by augmenting bone marrow progenitors in breast cancer. In this issue of the JCI, Colligan et al. demonstrate that BRQ restored terminal differentiation of MDSCs. Using in vivo models of immunotherapy-resistant breast cancer, the authors uncovered a mechanism by which BRQ promoted myeloid cell differentiation by limiting their suppressive function and enhancing the efficacy of immune checkpoint blockade therapy. The findings offer insight into the biogenesis of MDSCs, provide an alternative avenue for cancers that remain unresponsive to conventional therapies, and may be extended to future translational studies in patients.
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