Function Of CD40 Research Articles

Dysregulation of pseudouridylation in small RNAs contributes to papillary thyroid carcinoma metastasis

BackgroundPrevious studies have indicated that ψ-modified small RNAs play crucial roles in tumor metastasis. However, the ψ-modified small RNAs during metastasis of PTC are still unclear.MethodsWe compared the pseudouridine synthase 7 (PUS7) alteration between metastatic and non-metastatic PTCs, and investigated its correlation with clinicopathological features. Additionally, we employed a small RNA ψ modification microarray to examine the small RNA ψ modification profile in both metastatic and non-metastatic PTCs, as well as paired paracancerous tissues. The key molecule involved in ψ modification, pre-miR-8082, was identified and found to regulate the expression of CD47. Experiments in vitro were conducted to further investigate the function of PUS7 and CD47 in PTC.ResultsOur results demonstrated that PUS7 was down-regulated in PTC and was closely associated with metastasis. Moreover, the ψ modification of pre-miR-8082 was found to be decreased, resulting in down-expression of pre-miR-8082 and miR-8082, leading to the loss of the inhibitory effect on CD47, thereby promoting tumor migration.ConclusionsOur study demonstrates that PUS7 promotes the inhibition of CD47 and inhibits metastasis of PTC cells by regulating the ψ modification of pre-miR-8082. These results suggest that PUS7 and ψ pre-miR-8082 may serve as potential targets and diagnostic markers for PTC metastasis.

Cell autonomous functions of CD47 in regulating cellular plasticity and metabolic plasticity.

CD47 is a ubiquitously expressed cell surface receptor, which is widely known for preventing macrophage-mediated phagocytosis by interacting with signal regulatory protein α (SIRPα) on the surface of macrophages. In addition to its role in phagocytosis, emerging studies have reported numerous noncanonical functions of CD47 that include regulation of various cellular processes such as proliferation, migration, apoptosis, differentiation, stress responses, and metabolism. Despite lacking an extensive cytoplasmic signaling domain, CD47 binds to several cytoplasmic proteins, particularly upon engaging with its secreted matricellular ligand, thrombospondin 1. Indeed, the regulatory functions of CD47 are greatly influenced by its interacting partners. These interactions are often cell- and context-specific, adding a further level of complexity. This review addresses the downstream cell-intrinsic signaling pathways regulated by CD47 in various cell types and environments. Some of the key pathways modulated by this receptor include the PI3K/AKT, MAPK/ERK, and nitric oxide signaling pathways, as well as those implicated in glucose, lipid, and mitochondrial metabolism. These pathways play vital roles in maintaining tissue homeostasis, highlighting the importance of understanding the phagocytosis-independent functions of CD47. Given that CD47 expression is dysregulated in a variety of cancers, improving our understanding of the cell-intrinsic signals regulated by this molecule will help advance the development of CD47-targeted therapies.

Differential regulation by CD47 and thrombospondin-1 of extramedullary erythropoiesis in mouse spleen

Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from Cd47−/− mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in Cd47−/− spleens but significantly depleted in Thbs1−/− spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119−CD34+ progenitors and Ter119+CD34− committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in Thbs1−/− spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.

Differential regulation by CD47 and thrombospondin-1 of extramedullary erythropoiesis in mouse spleen.

Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from Cd47-/- mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in Cd47-/- spleens but significantly depleted in Thbs1-/- spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119-CD34+ progenitors and Ter119+CD34- committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in Thbs1-/- spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.

Abstract 106: Cd40 Is Required For B1b Cell Homeostasis In Atherosclerosis

The CD40-CD40L co-stimulatory dyad has been identified as critical player in atherosclerosis. Our previous work has shown that CD40 and CD40L have cell divergent effects on atherosclerosis. Deficiency of the CD40-CD40L dendritic cell-T cell axis decreased atherosclerosis via reducing T helper 1 responses, whereas deficiency of macrophages CD40 reduced atherosclerosis by enhancing efferocytosis and reducing necrotic core content. CD40 is highly expressed on B cells and interacts with CD40L on T cells to induce antibody production and T follicular helper cell responses. We therefore hypothesize that deletion of CD40 will reduce atherosclerosis. We aim to unravel the role of B cell CD40 in atherosclerosis. CD40 expression on B cell subsets was determined on peripheral blood mononuclear cells of patients and correlated with severity of coronary artery disease (CAD). Atherosclerosis was analyzed in CD19 Cre CD40 flfl ApoE -/- mice that were fed an atherogenic diet for 14 weeks. Patients with CAD showed a decrease in CD40 on their putative B1 cells, which was associated with increased plaque burden and decreased plaque fibrosis as detected by coronary intravascular ultrasound. Depletion of CD40 on B cells in ApoE -/- mice resulted in a decreased germinal center formation and inadequate IgM production as expected. However, in line with our patient data, absence of B cell-CD40 increased atherosclerosis. This was caused by a reduction in B1 cells and consequently a reduction in atheroprotective anti-oxidation specific epitope (OSE) IgMs. Transfer of CD40-competent B1b cells in B cell-CD40-deficient mice restored anti-OSE IgM levels and prevented the increase in atherosclerosis. CD40-deficient B1b cells have an altered mTOR signaling pathway, impaired mitochondrial function, excessive uptake of lipids, increased cellular stress and accelerated cell death. Data indicate that CD40-deficiency promotes phosphorylation of RAPTOR and protein kinase B (AKT). We have identified a novel function of CD40 on B1b cells. B1b cell-CD40 exerts an anti-atherogenic role by regulating B1b cell metabolic homeostasis via mTOR pathway. Further mechanistic insights into how CD40 mounts adequate atheroprotective anti-OSE IgM production are currently being investigated.

Progress in cancer research on the regulator of phagocytosis CD47, which determines the fate of tumor cells (Review).

Cluster of differentiation 47 (CD47) is a transmembrane protein that is widely and moderately expressed on the surface of various cells and can have an essential role in mediating cell proliferation, migration, phagocytosis, apoptosis, immune homeostasis and other related responses by binding to its ligands, integrins, thrombospondin-1 and signal regulatory protein α. The poor prognosis of cancer patients is closely associated with high expression of CD47 in glioblastoma, ovarian cancer, breast cancer, bladder cancer, colon cancer and hepatocellular carcinoma. Upregulation of CD47 expression facilitates the growth of numerous types of tumor cells, while downregulation of its expression promotes phagocytosis of tumor cells by macrophages, thereby limiting tumor growth. In addition, blocking CD47 activates the cyclic GMP-AMP (cGAMP) synthase/cGAMP/interferon gene stimulating factor signaling pathway and initiates an adaptive immune response that kills tumor cells. The present review describes the structure, function and interactions of CD47 with its ligands, as well as its regulation of phagocytosis and tumor cell fate. It summarizes the therapeutics, mechanisms of action, research advances and challenges of targeting CD47. In addition, this paper provides an overview of the latest therapeutic options for targeting CD47, such as chimeric antigen receptor (CAR) T-cells, CAR macrophages and nanotechnology-based delivery systems, which are essential for future clinical research on targeting CD47.

Moesin affects the plasma membrane expression and the immune checkpoint function of CD47 in human ovarian clear cell carcinoma

Among major histological subtypes of epithelial ovarian cancer, a higher incidence of ovarian clear cell carcinoma (OCCC) is observed in East Asian populations, particularly in Japan. Despite recent progress in the immune checkpoint inhibitors for a wide variety of cancer cell types, patients with OCCC exhibit considerably low response rates to these drugs. Hence, urgent efforts are needed to develop a novel immunotherapeutic approach for OCCC. CD47, a transmembrane protein, is overexpressed in almost all cancer cells and disrupts macrophage phagocytic activity in cancer cells. Ezrin-Radixin-Moesin (ERM) family member of proteins serve as scaffold proteins by crosslinking certain transmembrane proteins with the actin cytoskeleton, contributing to their plasma membrane localization. Here, we examined the role of ERM family in the plasma membrane localization and functionality of CD47 in OCCC cell lines derived from Japanese women. Confocal laser scanning microscopy analysis showed colocalization of CD47 with all three ERM in the plasma membrane of OCCC cells. RNA interference-mediated gene silencing of moesin, but not others, decreased the plasma membrane expression and immune checkpoint function of CD47, as determined by flow cytometry and in vitro phagocytosis assay using human macrophage-like cells, respectively. Interestingly, clinical database analysis indicated that moesin expression in OCCC was higher than that in other histological subtypes of ovarian cancers, and the expression of CD47 and moesin increased with the cancer stage. In conclusion, moesin is overexpressed in OCCC and may be the predominant scaffold protein responsible for CD47 plasma membrane localization and function in OCCC.

TRAF6 and TRAF2/3 Binding Motifs in CD40 Differentially Regulate B Cell Function in T-Dependent Antibody Responses and Dendritic Cell Function in Experimental Autoimmune Encephalomyelitis.

Expression of the costimulatory molecule CD40 on both B cells and dendritic cells (DCs) is required for induction of experimental autoimmune encephalomyelitis (EAE), and cell-autonomous CD40 expression on B cells is required for primary T-dependent (TD) Ab responses. We now ask whether the function of CD40 expressed by different cell types in these responses is mediated by the same or different cytoplasmic domains. CD40 has been reported to possess multiple cytoplasmic domains, including distinct TRAF6 and TRAF2/3 binding motifs. To elucidate the invivo function of these motifs in B cells and DCs involved in EAE and TD germinal center responses, we have generated knock-in mice containing distinct CD40 cytoplasmic domain TRAF-binding site mutations and have used these animals, together with bone marrow chimeric mice, to assess the roles that these motifs play in CD40 function. We found that both TRAF2/3 and TRAF6 motifs of CD40 are critically involved in EAE induction and demonstrated that this is mediated by a role of both motifs for priming of pathogenic T cells by DCs. In contrast, the TRAF2/3 binding motif, but not the TRAF6 binding motif, is required for B cell CD40 function in TD high-affinity Ab responses. These data demonstrate that the requirements for expression of specific TRAF-binding CD40 motifs differ for B cells or DCs that function in specific immune responses and thus identify targets for intervention to modulate these responses.

Evaluation of CD47 in the Suppressive Tumor Microenvironment and Immunotherapy in Prostate Cancer.

CD47 has high levels of expression in malignant cancer cells, which binds to SIRP-α to release the "don't eat me" signal and prevents mononuclear macrophages from phagocytosing the cells. Resistance to drugs and metastases are potential barriers for prostate cancer endocrine therapy. Although immunotherapy for tumors has developed rapidly in the last few decades, its effectiveness in treating prostate cancer is unsatisfactory. Prostate cancer has a high-expression level of CD47. Therefore, a novel approach for potential immunotherapy may be provided by investigating the relationship among CD47 and the infiltration of immune cells in the prostate carcinoma. The GEPIA database was utilized to compare the abundance of CD47 in malignant tissues with tissues that were normal. Furthermore, the function of CD47 in prostate carcinoma was assessed by CancerSEA. The association among CD47 and the tumor microenvironment was assessed utilizing the TISCH single cell data database. By using TIMER, the connection among CD47 and immunological invasion of prostate cancer was explored. Moreover, macrophages were cocultured with mouse prostate cancer cell RM-1 blocked by CD47 antibody to observe the changes in phagocytosis efficiency in vitro. Expression level of CD47 is upregulated in prostate carcinoma, and it is closely connected with prostate cancer's inadequate immune invasion. CD47 antibody blocking promotes macrophage phagocytosis of RM-1. Our research demonstrates a closely relationship among CD47 and the immunological microenvironment of prostate cancer, and blocking CD47 can promote macrophages to phagocytosis of prostate cancer cells. Therefore, CD47 may provide novel strategies for potential immunotherapy of prostate cancer.

A MD Simulation Prediction for Regulation of N-Terminal Modification on Binding of CD47 to CD172a in a Force-Dependent Manner.

Cancer cells can evade immune surveillance through binding of its transmembrane receptor CD47 to CD172a on myeloid cells. CD47 is recognized as a promising immune checkpoint for cancer immunotherapy inhibiting macrophage phagocytosis. N-terminal post-translated modification (PTM) via glutaminyl cyclase is a landmark event in CD47 function maturation, but the molecular mechanism underlying the mechano-chemical regulation of the modification on CD47/CD172a remains unclear. Here, we performed so-called "ramp-clamp" steered molecular dynamics (SMD) simulations, and found that the N-terminal PTM enhanced interaction of CD172a with CD47 by inducing a dynamics-driven contraction of the binding pocket of the bound CD172a, an additional constraint on CYS15 on CD47 significantly improved the tensile strength of the complex with or without PTM, and a catch bond phenomenon would occur in complex dissociation under tensile force of 25 pN in a PTM-independent manner too. The residues GLN52 and SER66 on CD172a reinforced the H-bonding with their partners on CD47 in responding to PTM, while ARG69 on CD172 with its partner on CD47 might be crucial in the structural stability of the complex. This work might serve as molecular basis for the PTM-induced function improvement of CD47, should be helpful for deeply understanding CD47-relevant immune response and cancer development, and provides a novel insight in developing of new strategies of immunotherapy targeting this molecule interaction.

Latest Findings on the Role of CD47 in Tumor Immune Evasion and Related Targeted Therapies

CD47 is an immunoglobulin that is overexpressed on the surface of a variety of cancer cells. CD47 forms a signaling complex with signal regulatory protein alpha (SIRPα), prompting the escape of cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed in many types of solid tumors and is associated with poor prognosis in patients. More and more studies have shown that inhibition of the CD47-SIRPα signaling pathway can promote adaptive immune responses and enhance the phagocytosis of tumor cells by macrophages. Humanized anti-CD47 IgG4 monoclonal antibody has been studied in clinical trials for the treatment of a variety of advanced solid tumors and lymphomas, demonstrating a sound safety profile and achieving partial remission in some patients. In this review we discuss the structure and function of CD47 and the mechanism of CD47 regulation in tumors, summarize the research progress in therapeutic antibody drugs targeting CD47 and a bottleneck in research that targeted drugs are more prone to result in serious adverse effects, and evaluated the potential of the applying CD47-SIRPα signaling pathway in anti-cancer therapy.

Roles of TSP1-CD47 signaling pathway in senescence of endothelial cells: cell cycle, inflammation and metabolism.

Endothelial cells (ECs) serve as a barrier with forming a monolayer lining in the surface of vascular system. Many mature cell types are post-mitotic like neurons, but ECs have the ability to grow during angiogenesis. Vascular endothelial growth factor (VEGF) stimulates growth of vascular ECs derived from arteries, veins, and lymphatics and induces angiogenesis. Senescence of ECs is regarded as a key contributor in aging-induced vascular dysfunction via evoking increase of ECs permeability, impairment of angiogenesis and vascular repair. Several genomics and proteomics studies on ECs senescence reported changes in gene and protein expression that directly correlate with vascular systemic disorder. CD47 functions as a signaling receptor for secreted matricellular protein thrombospondin-1 (TSP1) and plays an important role in several fundamental cellular functions, including proliferation, apoptosis, inflammation, and atherosclerotic response. TSP1-CD47 signaling is upregulated with age in ECs, concurrent with suppression of key self-renewal genes. Recent studies indicate that CD47 is involved in regulation of senescence, self-renewal and inflammation. In this review, we highlight the functions of CD47 in senescent ECs, including modulation of cell cycle, mediation of inflammation and metabolism by the experimental studies, which may provide CD47 as a potential therapeutic target for aging-associated vascular dysfunction.

Blockade of CD47 function attenuates restenosis by promoting smooth muscle cell efferocytosis and inhibiting their migration and proliferation

Cluster of differentiation 47 (CD47) plays an important role in the pathophysiology of various diseases including atherosclerosis, but its role in neointimal hyperplasia which contributes to restenosis, has not been studied. Using molecular approaches in combination with a mouse vascular endothelial denudation model, we studied the role of CD47 in injury-induced neointimal hyperplasia. We determined that thrombin induced CD47 expression both in human and mouse aortic smooth muscle cells (HASMCs and MASMCs). In exploring the mechanisms, we found that the protease-activated receptor 1 (PAR1)-Gα protein q/11 (Gαq/11)-phospholipase Cβ3 (PLCβ3)-nuclear factor of activated T cells c1 (NFATc1) signaling axis regulates thrombin-induced CD47 expression in HASMCs. Depletion of CD47 levels using its siRNA or interference of its function by its blocking antibody (bAb) blunted thrombin-induced migration and proliferation of HASMCs and MASMCs. In addition, we found that thrombin-induced HASMC migration requires CD47 interaction with integrin β3. On the other hand, thrombin-induced HASMC proliferation was dependent on CD47's role in nuclear export and degradation of CDK-interacting protein 1 (p21Cip1). In addition, suppression of CD47 function by its bAb rescued HASMC efferocytosis from inhibition by thrombin. We also found that vascular injury induces CD47 expression in intimal SMCs and that inhibition of CD47 function by its bAb, while alleviating injury-induced inhibition of SMC efferocytosis, attenuated SMC migration and proliferation resulting in reduced neointima formation. Thus, these findings reveal a pathological role for CD47 in neointimal hyperplasia.

CD47-Dependent Regulation of Immune Checkpoint Gene Expression and MYCN mRNA Splicing in Murine CD8 and Jurkat T Cells.

Elevated expression of CD47 in some cancers is associated with poor survival related to its function as an innate immune checkpoint when expressed on tumor cells. In contrast, elevated CD47 expression in cutaneous melanomas is associated with improved survival. Previous studies implicated protective functions of CD47 expressed by immune cells in the melanoma tumor microenvironment. RNA sequencing analysis of responses induced by CD3 and CD28 engagement on wild type and CD47-deficient Jurkat T lymphoblast cells identified additional regulators of T cell function that were also CD47-dependent in mouse CD8 T cells. MYCN mRNA expression was upregulated in CD47-deficient cells but downregulated in CD47-deficient cells following activation. CD47 also regulated alternative splicing that produces two N-MYC isoforms. The CD47 ligand thrombospondin-1 inhibited expression of these MYCN mRNA isoforms, as well as induction of the oncogenic decoy MYCN opposite strand (MYCNOS) RNA during T cell activation. Analysis of mRNA expression data for melanomas in The Cancer Genome Atlas identified a significant coexpression of MYCN with CD47 and known regulators of CD8 T cell function. Thrombospondin-1 inhibited the induction of TIGIT, CD40LG, and MCL1 mRNAs following T cell activation in vitro. Increased mRNA expression of these T cell transcripts and MYCN in melanomas was associated with improved overall survival.

CD47 halts Ptpn6-deficient neutrophils from provoking lethal inflammation.

Mice with SHP1 proteins, which have a single amino acid substitution from tyrosine-208 residue to asparagine (hereafter Ptpn6spin mice), develop an autoinflammatory disease with inflamed footpads. Genetic crosses to study CD47 function in Ptpn6spin mice bred Ptpn6spin × Cd47-/- mice that were not born at the expected Mendelian ratio. Ptpn6spin bone marrow cells, when transferred into lethally irradiated Cd47-deficient mice, caused marked weight loss and subsequent death. At a cellular level, Ptpn6-deficient neutrophils promoted weight loss and death of the lethally irradiated Cd47-/- recipients. We posited that leakage of gut microbiota promotes morbidity and mortality in Cd47-/- mice receiving Ptpn6spin cells. Colonic cell death and gut leakage were substantially increased in the diseased Cd47-/- mice. Last, IL-1 blockade using anakinra rescued the morbidity and mortality observed in the diseased Cd47-/- mice. These data together demonstrate a protective role for CD47 in tempering pathogenic neutrophils in the Ptpn6spin mice.

Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration.

In aging, skeletal muscle strength and regenerative capacity decline, due in part to functional impairment of muscle stem cells (MuSCs), yet the underlying mechanisms remain elusive. Here, we capitalize on mass cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs (CD47hi) with impaired regenerative capacity that predominate with aging. The prevalent CD47hi MuSC subset suppresses the residual functional CD47lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blockade of CD47 alternative polyadenylation or antibody blockade of thrombospondin-1/CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging.

A post-middle-age crisis for CD47 and THBS1 that turns into a vicious cycle.

In this issue of Cell Stem Cell, Porpiglia etal.1 report on alterations in CD47 and THBS1 expression and function in aged muscle stem cells that disrupt their regeneration capacity. Targeting THBS1-CD47 cross-signaling is sufficient to reverse sarcopenia and restore muscle mass and function in aged mice.

CD47 as a promising therapeutic target in oncology.

CD47 is ubiquitously expressed on the surface of cells and plays a critical role in self-recognition. By interacting with SIRPα, TSP-1 and integrins, CD47 modulates cellular phagocytosis by macrophages, determines life span of individual erythrocytes, regulates activation of immune cells, and manipulates synaptic pruning during neuronal development. As such, CD47 has recently be regarded as one of novel innate checkpoint receptor targets for cancer immunotherapy. In this review, we will discuss increasing awareness about the diverse functions of CD47 and its role in immune system homeostasis. Then, we will discuss its potential therapeutic roles against cancer and outlines, the possible future research directions of CD47- based therapeutics against cancer.

Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state.

CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac-/- compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis.

Cancer is still a major disease that is currently difficult for humans to overcome. When the expression of the cluster of differentiation 47 (CD47) is upregulated, tumor cells interact with the macrophage inhibitory receptor signal regulatory protein α (SIRPα) to transmit the "Don't eat me" signal, thereby avoiding phagocytosis by the macrophages. Therefore, when the CD47-SIRPα axis is inhibited, the macrophages' phagocytic function can be restored and can also exert antitumor effects. This Review mainly introduces recent advances in tumor therapy targeted on the CD47-SIRPα axis, including the antibody and fusion protein, small molecule, gene therapy, cell therapy, and drug delivery system, to inhibit the function of CD47 expressed on tumor cells and promote tumor phagocytosis by macrophages. In addition, this Review also summarizes the current approaches to avoid anemia, a common side effect of CD47-SIRPα inhibitions, and provides ideas for clinical transformation.