Phagocytic Signaling Research Articles

Facilitating cholangiocarcinoma inhibition by targeting CD47

Immune evasion is one of the mechanisms by which cancer cells acquire immunity during cancer development and progression. One of these is the increased expression of cluster of differentiation 47 (CD47), a transmembrane glycoprotein that protects cells from phagocytic elimination. The interaction between CD47 and signal regulatory protein alpha (SIRPα) on macrophages alleviates the phagocytic signal. The present group previously reported high CD47 expression in cholangiocarcinoma (CCA), a major health problem in Thailand and East Asia, and that blocking CD47 using anti-CD47 antibodies promoted the removal of CCA. However, the mechanism through which CD47 inhibition attenuates CCA growth remains unclear. This study explored the clinical significance of targeting CD47 in CCA. Expression levels of CD47 and the macrophage marker CD68 were determined in CCA tissues by immunohistochemistry and correlated with clinical parameters. The role of CD47 in CCA cells was established using CD47-deficient KKU-213A CCA clones in vitro and in vivo. The results showed that CD47 was highly expressed in CCA tissues and significantly correlated with lymph node metastasis (P = 0.038). Moderate-to-dense CD68-positive infiltrating cells in CCA tissues were significantly associated with shorter survival of patients (P = 0.019) and were an independent prognostic factor of CCA patients as determined by the Cox proportional hazard model (hazard ratio, 2.040; 95 % confidence interval, 1.109–3.752; P = 0.022). Three CD47-deficient KKU-213A clones (#19, #23, and #28) were generated. The elimination of CD47 did not affect cell proliferation but increased monocyte-derived macrophage-mediated phagocytosis in vitro. Decreased tumor weights and volumes were observed in mice injected with CD47-deficient CCA clones. This revealed a significant role for CD47 in CCA, with a focus on protecting cancer cells from macrophage phagocytosis.

Phosphatidylserine-incorporated exosome mimetics encapsulating CXCR3 antagonist alleviate osteoporosis.

Exosomes derived from mesenchymal stem cells are an active area of research due to their therapeutic potential in treating osteoporosis. To further harness their therapeutic performance in modulating bone resorption, we have equipped exosomes with osteoclast-targeting moieties on their surface as well as chemokine receptor antagonists blocking osteoclast recruitment. Phosphatidylserine (PS), a membrane lipid exerting immunosuppressive and phagocytic signals, was incorporated in the membrane of exosome mimetics (EMs) to achieve a marked affinity for osteoclast precursors and potential anti-resorptive effects. We also aimed to tackle a CXCL9-CXCR3 ligand-receptor axis, a critical signaling axis in regulating osteoclast precursor recruitment and differentiation at bone resorption sites, by encapsulating a chemical antagonist of CXCR3, AMG487, in the PS-incorporated EMs (PS-EMs). The osteoclast-targeting PS-EMs loaded with AMG487 effectively protected against bone loss in an ovariectomized mouse model. Our findings demonstrate the great promise of PS-EMs as anti-resorptive nanotherapies for alleviating osteoporosis.

Exogenous non-coding dsDNA-dependent trans-activation of phagocytes augments anti-tumor immunity

Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway. We observe that rHSVs expressing STING and/or cGAS replicate inefficiently yet retain invivo anti-tumor activity, independent of oncolytic activity requisite on the trans-activation of extrinsic STING signaling in phagocytes by engulfed microbial dsDNA species. Accordingly, the invivo effects of virotherapy could be simulated by nanoparticles incorporating non-coding dsDNA species, which comparably elicit the trans-activation of phagocytes and augment the efficacy of established cancer treatments including checkpoint inhibition and radiation therapy. Our results help elucidate mechanisms of virotherapeutic anti-tumor activity as well as provide alternate strategies to treat cancer.

Development of cationic solid lipid nanoparticles incorporating cholesteryl-9-carboxynonanoate (9CCN) for delivery of antagomiRs to macrophages

Lipid-based nanoparticles are a useful tool for nucleic acids delivery and have been regarded as a promising approach for diverse diseases. However, off-targets effects are a matter of concern and some strategies to improve selectivity of solid lipid nanoparticles (SLNs) were reported. The goal of this study was to test formulations of SLNs incorporating lipid cholesteryl-9-carboxynonanoate (9CCN) as “eat-me” signal to target antagomiR oligonucleotides to macrophages. We formulate four SLNs, and those with a mean diameter of 200 nm and a Z-potential values between 25 and 40 mV, which allowed the antagomiR binding, were selected for in vitro studies. Cell viability, transfection efficiency and cellular uptake assays were performed within in vitro macrophages using flow cytometry and confocal imaging and the SLNs incorporating 25 mg of 9CCN proved to be the best formulation. Subsequently, we used a labeled antagomiR to study tissue distribution in in-vivo ApoE-/- model of atherosclerosis. Using the ApoE-/- model we demonstrated that SLNs with phagocytic signal 9-CCN target macrophages and release the antagomiR cargo in a selective way.

Nuclear Factor κB Signaling Deficiency in CD11c-Expressing Phagocytes Mediates Early Inflammatory Responses and Enhances Mycobacterium tuberculosis Control.

Early innate immune responses play an important role in determining the protective outcome of Mycobacterium tuberculosis (Mtb) infection. Nuclear factor κB (NF-κB) signaling in immune cells regulates the expression of key downstream effector molecules that mount early antimycobacterial responses. Using conditional knockout mice, we studied the effect of abrogation of NF-κB signaling in different myeloid cell types and its impact on Mtb infection. Our results show that the absence of IKK2-mediated signaling in all myeloid cells resulted in increased susceptibility to Mtb infection. In contrast, the absence of IKK2-mediated signaling in CD11c+ myeloid cells induced early proinflammatory cytokine responses, enhanced the recruitment of myeloid cells, and mediated early resistance to Mtb. Abrogation of IKK2 in MRP8-expressing neutrophils did not affect disease pathology or Mtb control. Thus, we describe an early immunoregulatory role for NF-κB signaling in CD11c-expressing phagocytes and a later protective role for NF-κB in LysM-expressing cells during Mtb infection.

Intracellular and extracellular synergistic therapy for restoring macrophage functions via anti-CD47 antibody-conjugated bifunctional nanoparticles in atherosclerosis

Atherosclerosis is a significant contributor to global cardiovascular disease. Reducing the formation of atherosclerotic plaque effectively can lead to a decrease in cardiovascular diseases. Therefore, controlling macrophage function is crucial. This study presents the creation of a bifunctional nanoparticle that is specific to macrophages to achieve intracellular and extracellular synergistic therapy for restoring macrophage functions. The nanoparticle is conjugated with anti-CD47 antibody to modulate extracellular CD47-SIRPα phagocytic signaling axis on the outer surface of macrophages and encapsulates the NLRP3 inhibitor (CY-09) to regulate intracellular inflammation response of macrophages. The results showed that the nanoparticles accumulate in the atherosclerotic plaque, alter macrophage phagocytosis, inhibit NLRP3 inflammasome activation, and decrease the plaque burden in Apoe−/− mice whilst ensuring safety. Examination of single-cell RNA sequencing indicates that this multifunctional nanoparticle decreases the expression of genes linked to inflammation and manages inflammatory pathways in the plaque lesion. This study proposes a synergistic therapeutic approach that utilizes a bifunctional nanoparticle, conjugated with anti-CD47, to regulate the microenvironment of plaques.

Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages.

Targeting lipopolysaccharide (LPS)/toll-like receptor4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPKand PI3K/Akt or modulating LPS-related gene expression.

Single-cell transcriptomics reveals ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia exerts antitumor effects by alleviating macrophage suppression in breast cancer

The potential of Ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia (FVIO-MHT) in solid tumor therapy has been demonstrated. However, the impact of FVIO-MHT on the tumor microenvironment (TME) remains unclear. This study utilized single-cell transcriptome sequencing to examine the alterations in the TME in response to FVIO-MHT in breast cancer. The results revealed the cellular composition within the tumor microenvironment (TME) was primarily modified due to a decrease in tumor cells and an increased infiltration of myeloid cells. Subsequently, an enhancement in active oxygen (ROS) metabolism was observed, indicating oxidative damage to tumor cells. Interestingly, FVIO-MHT reprogrammed the macrophages’ phenotypes, as evidenced by alterations in the transcriptome characteristics associated with both classic and alternative activated phenotypes. And an elevated level of ROS generation and oxidative phosphorylation suggested that activated phagocytosis and inflammation occurred in macrophages. Additionally, cell–cell communication analysis revealed that FVIO-MHT attenuated the suppression between tumor cells and macrophages by inhibiting phagocytic checkpoint and macrophage migration inhibitory factor signaling pathways. Inhibition of B2m, an anti-phagocytosis checkpoint, could promote macrophage-mediated phagocytosis and significantly inhibit tumor growth. These data emphasize FVIO-MHT may promote the antitumor capabilities of macrophages by alleviating the suppression between tumor cells and macrophages.

Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages.

Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and "educate" macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.

Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy

Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.

Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.

Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed of glycerophospholipids, sphingolipids and cholesterol, in which proteins are embedded. Glycerophospholipids and sphingolipids freely move laterally, whereas transverse movement between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins - flippases and scramblases - mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases.

The spatial resolution limit of phagocytosis

Antibody-opsonized bacteria interact with Fc receptors in macrophages and trigger signaling cascades, which induce phagocytosis. The signaling pathways ultimately lead to actin polymerization that induces the protrusion of the membrane around the bacterium until it is completely engulfed. Although many proteins involved in the phagocytic cup formation have already been identified, it is still unclear how far the initial stimulus created by the bacterium-cell contact propagates in the cell. We hypothesize that this spreading distance is closely related to the spatial resolution limit of phagocytosis, the smallest distance in which two stimuli can be differentiated. Here, we probe this resolution limit by using holographic optical tweezers to attach pairs of immunoglobulin G-coated polystyrene microparticles (as models for opsonized bacteria) to murine macrophages in distances ranging from zero to several micrometers.By using 2-μm-sized particles, we found that the particles can be internalized jointly into one phagosome if they are attached to the cell very close together, but that they are taken up separately if they are attached far from each other. To explain this, we developed a model of the signaling process, which predicts the probabilities for separate uptake for different particle sizes and distances using cellular parameters including the average receptor distance. We tested the model by measuring the separate uptake probabilities for particles with a diameter of 1 to 3 μm and for cells with reduced numbers of Fcγ receptors and found very good agreement. Our model shows that the phagocytic uptake behavior can be explained by assuming an effective phagocytic signaling range of about 500 nm. Interestingly, this value corresponds to the lower size limit of phagocytosis.Our work provides quantitative access to spatial parameters of cellular signaling during phagocytosis and thereby contributes to a more quantitative understanding of cellular information processing.

Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.

The delivery of pathogens to lysosomes for degradation provides an important defense against infection. Degradation is enhanced when LC3 is conjugated to endosomes and phagosomes containing pathogens to facilitate fusion with lysosomes. In phagocytic cells, TLR signaling and Rubicon activate LC3-associated phagocytosis (LAP) where stabilization of the NADPH oxidase leads to sustained ROS production and raised vacuolar pH. Raised pH triggers the assembly of the vacuolar ATPase on the vacuole membrane where it binds ATG16L1 to recruit the core LC3 conjugation complex (ATG16L1:ATG5-12). This V-ATPase-ATG16L1 axis is also activated in nonphagocytic cells to conjugate LC3 to endosomes containing extracellular microbes. Pathogens provide additional signals for recruitment of LC3 when they raise vacuolar pH with pore-forming toxins and proteins, phospholipases, or specialized secretion systems. Many microbes secrete virulence factors to inhibit ROS production and/or the V-ATPase-ATG16L1 axis to slow LC3 recruitment and avoid degradation in lysosomes.

Sphingolipids: A double-edged sword in the defense against Mycobacterium tuberculosis.

Abstract Mycobacterium tuberculosis (Mtb) is a pathogen with a massive global health impact, and yet fundamental questions remain regarding the underlying mechanisms of its entry and subversion of innate immune mechanisms – particularly the manners in which host lipids influence the course of an infection. This pathogen gains entry to host alveolar macrophages via phagocytosis and, within the phagosome, Mtb perturbs host lipid metabolism and distribution. Here, we've shown that Mtb relies on an intact sphingolipid biosynthesis pathway to gain entry to host cells but that sphingolipids restrict the intracellular growth of this pathogen. We used genetic ablation and small molecule inhibition to perturb sphingolipid biosynthesis, resulting in reduced Mtb uptake across multiple phagocytic cell types without affecting receptor mediated endocytosis. Mechanistically, we visualized the dynamics of several signaling events during phagocytosis to demonstrate that sphingolipid deficiency results in poor initiation of phagocytic signaling. Intriguingly, sphingolipid inhibition at later stages of infection may result in enhanced intracellular Mtb growth and accelerated lysosomal damage and subsequent phagolysosomal escape. This study has revealed that the sphingolipid family may constitute a double-edged sword which plays multiple roles during Mtb infection. In understanding the interplay between Mycobacterium tuberculosis and host factors such as sphingolipids, we hope to identify novel methods of treatment for this ancient and global pathogen. Supported by grants from NIH (R21 3R21AI124225-01A1 and R01 1R01AI14154 9-01A1)

Src kinase mediates coelomocytes phagocytosis via interacting with focal adhesion kinase in Vibrio splendidus challenged Apostichopus japonicus

Immune cells have many efficient ways to participate in the host immunity, including phagocytosis, which is an important pathway to eliminate pathogens. Only β-integrin-mediated phagocytosis pathways have been confirmed in Apostichopus japonicus. The Src family kinases (SFKs), a class of non-receptor tyrosine kinases plays an important role in the regulation of phagocytic signals in invertebrates. However, the SFK-mediated phagocytic mechanism is largely unknown in A. japonicus. In this study, a novel SFK homologue (AjSrc) with a conservative SH3 domain, an SH2 domain, and a tyrosine kinase domain was identified from A. japonicus. Both gene and protein expression of AjSrc and phosphorylation levels increased under Vibrio splendidus challenged, reaching the highest level at 24 h. Knock-down of AjSrc could depress coelomocytes' phagocytosis by 25% compared to the control group. To better understand the mechanism of AjSrc-mediated phagocytosis, focal adhesion kinase (FAK) was identified by a Co-immunoprecipitation experiment to be verified as an interactive protein of AjSrc. The phagocytosis rates of coelomocytes were decreased by 33% and 37% in AjFAK and AjSrc + AjFAK interference groups compared with the control group, respectively. Furthermore, the phosphorylation level of AjFAK was increased and reached the maximum level at 24 h post V. splendidus infection, as the same as that of AjSrc. Our results suggested that AjSrc could mediate V. splendidus-induced coelomocytes' phagocytosis via interacting with AjFAK and co-phosphorylation. This study enriched the mechanism of phagocytosis in echinoderm and provided the new theoretical foundation for disease control of sea cucumber.

Phospholipid Scramblases: Role in Cancer Progression and Anticancer Therapeutics.

Phospholipid scramblases (PLSCRs) that catalyze rapid mixing of plasma membrane lipids result in surface exposure of phosphatidyl serine (PS), a lipid normally residing to the inner plasma membrane leaflet. PS exposure provides a chemotactic eat-me signal for phagocytes resulting in non-inflammatory clearance of apoptotic cells by efferocytosis. However, metastatic tumor cells escape efferocytosis through alteration of tumor microenvironment and apoptotic signaling. Tumor cells exhibit altered membrane features, high constitutive PS exposure, low drug permeability and increased multidrug resistance through clonal evolution. PLSCRs are transcriptionally up-regulated in tumor cells leading to plasma membrane remodeling and aberrant PS exposure on cell surface. In addition, PLSCRs interact with multiple cellular components to modulate cancer progression and survival. While PLSCRs and PS exposed on tumor cells are novel drug targets, many exogenous molecules that catalyze lipid scrambling on tumor plasma membrane are potent anticancer therapeutic molecules. In this review, we provide a comprehensive analysis of scramblase mediated signaling events, membrane alteration specific to tumor development and possible therapeutic implications of scramblases and PS exposure.

Analysis of phagocytosis by mIgM+ lymphocytes depending on monoclonal antibodies against IgM of largemouth bass (Micropterus salmoides)

The phagocytic actives of B cells in fish have been proven in recent years. In this study, five positive hybridomas secreting monoclonal antibodies (MAbs) against largemouth bass IgM were produced. Indirect immunofluorescence assay (IFA) demonstrated that five MAbs could specifically recognize membrane-bound IgM (mIgM) molecule of largemouth bass. Indirect ELISA and Western blotting analysis showed that all the five MAbs had no cross-reactions with the other two teleost IgMs. Flow cytometry analysis (FCM) revealed that the percentages of largemouth bass mIgM+ lymphocytes in head kidney, peripheral blood and spleen were 51.66 ± 0.608%, 16.5 ± 1.235% and 42.92 ± 1.091%, respectively. In addition, the phagocytosis rates of mIgM + lymphocytes ingesting Nocardia seriolae from head kidney, peripheral blood and spleen were calculated to be 5.413 ± 0.274%, 16.6 ± 0.289% and 26.3 ± 0.296%, respectively. The qPCR results of sorted cells indicated that most inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-12β, IL-34, IL-10), chemokine (CXCL12), chemokines receptors (CXCR2, CXCR4) and genes (FcγRⅠa, NCF1, CFL, ARP2/3, CD45, Syk, MARCKS) related to FcγR-mediated phagocytic signaling pathway in phagocytic mIgM+ lymphocytes were up-regulated significantly (P < 0.05). Taken together, the results suggested that the MAb (MM06H) produced in this paper could be used as a tool to study mIgM+ lymphocytes of largemouth bass, and FcγR may participate in the phagocytosis of mIgM+ lymphocytes, which is helpful to further study the role of mIgM+ lymphocytes in innate immunity.

Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity.

Exposure to exogenous particles found as airborne contaminants or endogenous particles that form by crystallization of certain nutrients can activate inflammatory pathways and potentially accelerate autoimmunity onset and progression in genetically predisposed individuals. The first line of innate immunological defense against particles are myeloid-lineage phagocytes, namely macrophages and neutrophils, which recognize/internalize the particles, release inflammatory mediators, undergo programmed/unprogrammed death, and recruit/activate other leukocytes to clear the particles and resolve inflammation. However, immunogenic cell death and release of damage-associated molecules, collectively referred to as “danger signals,” coupled with failure to efficiently clear dead/dying cells, can elicit unresolved inflammation, accumulation of self-antigens, and adaptive leukocyte recruitment/activation. Collectively, these events can promote loss of immunological self-tolerance and onset/progression of autoimmunity. This review discusses critical molecular mechanisms by which exogenous particles (i.e., silica, asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts) and endogenous particles (i.e., monosodium urate, cholesterol crystals, calcium-containing salts) may promote unresolved inflammation and autoimmunity by inducing toxic responses in myeloid-lineage phagocytes with emphases on inflammasome activation and necrotic and programmed cell death pathways. A prototypical example is occupational exposure to respirable crystalline silica, which is etiologically linked to systemic lupus erythematosus (SLE) and other human autoimmune diseases. Importantly, airway instillation of SLE-prone mice with crystalline silica elicits severe pulmonary pathology involving accumulation of particle-laden alveolar macrophages, dying and dead cells, nuclear and cytoplasmic debris, and neutrophilic inflammation that drive cytokine, chemokine, and interferon-regulated gene expression. Silica-induced immunogenic cell death and danger signal release triggers accumulation of T and B cells, along with IgG-secreting plasma cells, indicative of ectopic lymphoid tissue neogenesis, and broad-spectrum autoantibody production in the lung. These events drive early autoimmunity onset and accelerate end-stage autoimmune glomerulonephritis. Intriguingly, dietary supplementation with ω-3 fatty acids have been demonstrated to be an intervention against silica-triggered murine autoimmunity. Taken together, further insight into how particles drive immunogenic cell death and danger signaling in myeloid-lineage phagocytes and how these responses are influenced by the genome will be essential for identification of novel interventions for preventing and treating inflammatory and autoimmune diseases associated with these agents.

Novel Mechanisms of Exosome-Mediated Phagocytosis of Dead Cells in Injured Heart.

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MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites.

Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.