Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation. 

Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects

Background The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC. Methods Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9+TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays. Results Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9+TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9+TAMs with protumorigenic phenotypes. Siglec-9+TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8+T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8+T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9+TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8+T cells in tissues with higher Siglec-9+TAMs. Conclusions Siglec-9+TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9+TAMs as a therapeutic target is worth further exploration.

Siglec-9+ tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer

Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases. 

Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms to resolve inflammation are intact but become defective in patients, resulting in lack of resolution mediators and unresolved chronic inflammation. Docosahexaenoic acid (DHA) metabolism being impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Restoration of MaR1 by its exogenous administration in EAE mice propagated inflammatory resolution and had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN-γ+) into the CNS. It significantly reduced the proinflammatory cytokine IL17 and promoted an anti-inflammatory response via IL10 and IL4. Neutralization of IL10 abolished the protective effect of MaR1 in EAE confirming IL10 is mediating MaR1 effect in EAE. Furthermore, it improved the pathophysiology and exerted neuroprotective effects by mitigating disease signs in EAE as evidenced by lower levels of NFL in the plasma of treated group compared to control and higher MBP expression in the brain from the MaR1 treated mice, decreased inflammatory infiltrates, and less demyelination and vacuolization in the spinal cord tissue sections of treated mice. SCENITH data confirmed that MaR1 maintains myelin by regulating oligodendrocyte metabolism. Also, it induces metabolic reprogramming in infiltrating CD4 cells and macrophages, which modulate their phenotype. Metabolic changes induced macrophages by MaR1 restores the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models and induces metabolic reprogramming in disease associated cell-types, promotes efferocytosis, implying that it could be a new therapeutic molecule in MS and other autoimmune diseases. Highlights Inflammation is dysregulated in EAE due to impaired synthesis of DHA derived proresolving lipid mediator MaR1. Administration of the resolution agonist MaR1 propagates resolution processes and improves neurological outcome in RR model of EAE. MaR1 ameliorates clinical signs of EAE by attenuating pro-inflammatory cytokine IL17 mediated response and promoting anti-inflammatory response through IL10. MaR1 supplementation improves the pathophysiology in EAE and shows neuroprotection as indicated by the lower levels of NFL in the plasma and higher expression of MBP in the brain of treated mice. MaR1 induces metabolic reprogramming in disease-associated cell types. MaR1 promotes efferocytosis in EAE through metabolic reprogramming of macrophages. Significance Inflammatory process is a protective response to several challenges like injury or infection. However, it must resolve over time to maintain tissue homeostasis. Impaired or delayed resolution leads to damaging effects, including chronic inflammation, tissue damage, and disease progression as occurs in multiple sclerosis (MS). We report that inflammation is dysregulated in preclinical animal model of MS, experimental autoimmune encephalomyelitis (EAE), partially due to impaired synthesis of proresolving lipid mediators. We show that the administration of the resolution agonist known as maresin 1 (MaR1) in EAE actively propagates resolution processes and improves neurological outcome. We conclude that MaR1 is a potential interventional candidate to attenuate dysregulated inflammation and to restore neurological deficits in EAE. Graphical abstract

Pro-resolution lipid mediator maresin-1 ameliorates inflammation, promotes neuroprotection, and prevents disease progression in experimental models of multiple sclerosis

Engulfment and cell motility protein (ELMO) was identified as a novel, evolutionarily conserved upstream regulator of the RAC signaling pathway in mammals, which was essential for diverse physiological and pathological processes of cells, such as phagocytosis and cell migration. However, the functions and the underlying mechanisms of ELMO1 are generally poorly understood in invertebrates. In this study, we found that the endocytosis and GTP activity were significantly enriched in AjELMO1-interfered coelomocytes of Apostichopus japonicus by RNA-seq. Moreover, overexpression or interference of AjELMO1 significantly altered the coelomocyte phagocytosis levels induced by Vibrio splendidus AJ01, leading to an increase and decrease in the intracellular AJ01 burden by flow cytometry and bacteriophage plate counting in vivo and in vitro. Further functional analysis with different endocytosis inhibitors treatment revealed that AjELMO1 mediated AJ01 internalization via the actin-dependent endocytic pathways through the changes of F-actin/G-actin, but not the clathrin-, macropinocytosisi-, and dynamin-dependent endocytic pathways. The dedicator of cytokinesis protein 1 (AjDOCK180) was identified as an interacting protein of AjELMO1 using co-IP and GST-Pull down followed by mass spectrometry identification. Further function analysis also revealed that AjDOCK180 promotes coelomocyte phagocytosis through the actin endocytosis pathway via the changes in the phagocytosis levels, the intracellular AJ01 burden, and the ratio of F-actin/G-actin in coelomocytes. Additionally, we found that the phagocytic activity in sea cucumber coelomocytes promoted by AjELMO1 can be blocked by interference with AjDOCK180. Altogether, our data demonstrate that AjELMO1-AjDOCK180 is involved in resisting AJ01 infection via medicating coelomocyte phagocytosis through the actin-dependent pathway. 

ELMO interacts with DOCK180 to enhance coelomocyte phagocytosis in Vibrio splendidus challenged Apostichopus japonicus

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.

Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.

Defining the molecular and genetic basis for heart rate regulation and for susceptibility to atrial arrhythmias has been challenging due to the complexity of the human sinoatrial node (SAN), a tiny structure with limiting numbers of several distinct pacemaker cardiomyocyte (PC) subtypes in a spatially patterned array. Here we describe a novel method to derive large numbers of human PCs from human induced pluripotent stem cells (hiPSCs) that recapitulates key features of SAN development including differentiation into anatomically and functionally distinct PC subtypes of the SAN. Single cell (sc) RNA-sequencing, sc-ATAC-sequencing, and time course analyses of cellular differentiation were used to define epigenetic and transcriptomic signatures of cellular specialization within the SAN, and to identify transcriptional pathways important for PC differentiation. Intersection of our multi-omics datasets with existing human genome wide association studies uncovered regulatory elements with differential accessibility in different PC subtypes that harbored SNPs that associated with human heart rate regulation and susceptibility to atrial fibrillation, enabling disease gene discovery and prioritization.

/pdf/single-cell-multi-omics-of-an-ipsc-model-of-human-sinoatrial-flv3ls3b.pdf

Single Cell Multi-Omics of an iPSC Model of Human Sinoatrial Node Development Reveals Genetic Determinants of Heart Rate and Arrhythmia Susceptibility

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Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.

Single Cell Multi-Omics of an iPSC Model of Human Sinoatrial Node Development Reveals Genetic Determinants of Heart Rate and Arrhythmia Susceptibility