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As the world is severely affected by COVID-19 pandemic, the use of chloroquine and hydroxychloroquine in prevention or for the treatment of patients is allowed in multiple countries but remained at the center of much controversy in recent days. This review describes the properties of chloroquine and hydroxychloroquine, and highlights not only their anti-viral effects but also their important immune-modulatory properties and their well-known use in autoimmune diseases, including systemic lupus and arthritis. Chloroquine appears to inhibit SARS virus' replication and to interfere with SARS-CoV2 receptor (ACE2). Chloroquine and hydroxychloroquine impede lysosomal activity and autophagy, leading to a decrease of antigen processing and presentation. They are also known to interfere with endosomal Toll-like receptors signaling and cytosolic sensors of nucleic acids, which result in a decreased cellular activation and thereby a lower type I interferons and inflammatory cytokine secretion. Given the antiviral and anti-inflammatory properties of chloroquine and hydroxychloroquine, there is a rational to use them against SARS-CoV2 infection. However, the anti-interferon properties of these molecules might be detrimental, and impaired host immune responses against the virus. This duality could explain the discrepancy with the recently published studies on CQ/HCQ treatment efficacy in COVID-19 patients. Moreover, although these treatments could be an interesting potential strategy to limit progression toward uncontrolled inflammation, they do not appear sufficiently potent to control the whole inflammatory process in COVID-19, and more targeted and/or potent therapies should be required at least in add-on.

Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS. Primary antiphospholipid syndrome (PAPS) is a clotting disorder attributed to autoreactive antibodies produced by B cells. Here the authors show, using single cell omics and B cell repertoire data, that autoreactive B cells originate from the natural B cell repertoire and escape germinal center selection to persist in PAPS patient via potential dysregulation of mTORC1 and MYC pathways.

Emerging evidence suggests that the function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyze lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and show that lysosome spreading scales with melanoma aggressiveness. Peripheral lysosomes promote matrix degradation and cell invasion which is directly linked to the lysosomal and cell transcriptional programs. Using chemo-genetical control of lysosome positioning, we demonstrate that perinuclear clustering impairs lysosome secretion, matrix degradation and invasion. Impairing lysosome spreading significantly reduces invasive outgrowth in two in vivo models, mouse and zebrafish. Our study provides a direct demonstration that lysosome positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting its potential utility for diagnosis of metastatic melanoma. The function and position of organelles are pivotal for tumor cell dissemination. Here the authors use melanoma patient samples and animal models to show that peripheral localization of lysosomes promotes metastasis by favoring lysosome exocytosis and cell invasion.

Systemic sclerosis (SSc) is an autoimmune disease characterized by antinuclear antibody production, which has been linked to an excess of apoptotic cells, normally eliminated by macrophages through efferocytosis. Additionally, circulating levels of CXCL4, a novel SSc biomarker, correlate with more severe fibrotic manifestations of the disease. Considering the defective efferocytosis of macrophages in SSc and the CXCL4-related M4 macrophage phenotype, we hypothesized that CXCL4 could be involved in the alteration of phagocytic functions of macrophages in SSc, including LC3-associated phagocytosis (LAP), another phagocytic process requiring autophagy proteins and contributing to immune silencing. In this study, CXCL4 levels were measured by ELISA in the serum of SSc patients, and also in the serum and lungs of C57BL/6J SSc mice induced by intradermal injections of hypochloric acid (HOCl) or Bleomycin (BLM), with evaluation of M4 markers. Circulating monocytes from healthy donors were also differentiated into M4 monocytes-derived macrophages (MDMs) in the presence of recombinant CXCL4. In M4-MDMs, phagocytosis of fluorescent beads and expression level of efferocytic receptors were evaluated by flow cytometry , while efferocytosis of pHrodo-stained apoptotic Jurkat cells was evaluated by real-time fluorescence microscopy. LAP quantification was made by fluorescence microscopy in M4-MDMs exposed to IgG-coated beads as well as apoptotic Jurkat cells. Our results demonstrated that efferocytosis was significantly reduced in M0-MDMs from healthy donors exposed to the CXCL4-rich plasma of SSc patients. expression was increased in the lungs of both SSc-mouse models, along with elevated M4 markers, while efferocytosis of BLM-mice alveolar macrophages was decreased. , M4-MDMs exhibited reduced efferocytosis compared to M0-MDMs, notably attributable to lower CD36 receptor expression and impaired phagocytosis capacities, despite enhanced LAP. Autophagic gene expression was increased both in SSc MDMs and in BLM mice, thus acting as a potential compensatory mechanism. Altogether, our results support the role of CXCL4 on the impaired efferocytosis capacities of human macrophages from SSc patients and in SSc mice.

Stimulator of Interferon Gene (STING), a key player of antimicrobial immune responses, has emerged as a promising target to mitigate inflammation and cancer. Following STING activation, proinflammatory molecules and type I Interferons (IFN) are released thus favoring the establishment of effective immune responses and adaptive immunity. Autophagy has been proposed to negatively regulate STING signaling. While STING activation drives microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) lipidation, the underlying mechanisms and functional consequences remain however incompletely defined. Especially, the consequences of STING-associated Conjugation of autophagy related (ATG) 8 to Single Membranes (CASM) in the control of immune responses remain elusive. Using innate and adaptive cells specifically inactivated for autophagy or CASM, we found that STING agonists primarily trigger CASM over autophagy. While STING-associated autophagy exerts negative feedback on the STING pathway and downstream type I IFN and pro-inflammatory responses, with different underlying molecular mechanisms between immune cells, STING-driven CASM potentiates NFBκ-associated TNF production. These results overall uncover a new function of CASM and underscore the relevance of both CASM and autophagy in shaping STING signaling.Competing Interest StatementLionel Apetoh is a consultant for Brenus-Pharma. Lionel Apetoh performed consultancy work for Roche, Merck, Bristol-Myers Squibb, and Orega Biotech and was a recipient of a research grant from Sanofi. Oliver Florey reported non-financial support from Casma Therapeutics during the conduct of the study; personal fees from Casma Therapeutics outside the submitted work. No potential conflict of interest was reported by other authors regarding the submitted work.

Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called “noncanonical” autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly in ATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment. Polymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE While autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc We show here that autophagy is comparable between PBMCs from patients and matched controls We find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients As LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation

Emerging evidences suggest that function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyzed lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in patient-derived melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in two distinct in vivo models (mouse and zebrafish) significantly reduces invasive outgrowth. Our study provides a direct demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting that lysosome positioning could potentially be used for the diagnosis of metastatic melanoma.

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs), a proliferating skin DC subset with extended lifespan. Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors, in line with a reduction of epidermal nerves upon LC depletion. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.Competing Interest StatementThe authors have declared no competing interest.Footnotes* As compared to the first version, we have (1) acknowledged the apoptosis affecting Langerhans cells, (2) further demonstrated the involvement of ferroptosis and (3) clarified the outcome of inflammation-inducing experiments.