Despite extensive mapping of long noncoding RNAs in immune cells, their function in vivo remains poorly understood. In this study, we identify over 100 long noncoding RNAs that are differentially expressed within 24 h of Th1 cell activation. Among those, we show that suppression of Malat1 is a hallmark of CD4⁺ T cell activation, but its complete deletion results in more potent immune responses to infection. This is because Malat1^−/− Th1 and Th2 cells express lower levels of the immunosuppressive cytokine IL-10. In vivo, the reduced CD4⁺ T cell IL-10 expression in Malat1^−/−mice underpins enhanced immunity and pathogen clearance in experimental visceral leishmaniasis (Leishmania donovani) but more severe disease in a model of malaria (Plasmodium chabaudi chabaudi AS). Mechanistically, Malat1 regulates IL-10 through enhancing expression of Maf, a key transcriptional regulator of IL-10. Maf expression correlates with Malat1 in single Ag-specific Th cells from P. chabaudi chabaudi AS–infected mice and is downregulated in Malat1^−/− Th1 and Th2 cells. The Malat1 RNA is responsible for these effects, as antisense oligonucleotide-mediated inhibition of Malat1 also suppresses Maf and IL-10 levels. Our results reveal that through promoting expression of the Maf/IL-10 axis in effector Th cells, Malat1 is a nonredundant regulator of mammalian immunity. Key Points Malat1 is suppressed during Th1 and Th2 differentiation. Malat1 loss suppresses IL-10 and Maf expression in effector Th cells. Malat1^−/− mice mount enhanced immune responses in leishmaniasis and malaria models.

Visceral leishmaniasis is an important yet neglected parasitic disease caused by infection with Leishmania donovani or L infantum. Disease manifestations include fever, weight loss, hepatosplenomegaly, immune dysregulation, and extensive hematological complications. Thrombocytopenia is a dominant hematological feature seen in both humans and experimental models, but the mechanisms behind this infection-driven thrombocytopenia remain poorly understood. Using a murine model of experimental visceral leishmaniasis (EVL), we demonstrated a progressive decrease in platelets from day 14 after infection, culminating in severe thrombocytopenia by day 28. Plasma thrombopoietin (TPO) levels were reduced in infected mice, at least in part because of the alterations in the liver microenvironment associated with granulomatous inflammation. Bone marrow (BM) megakaryocyte cytoplasmic maturation was significantly reduced. In addition to a production deficit, we identified significant increases in platelet clearance. L donovani–infected splenectomized mice were protected from thrombocytopenia compared with sham operated infected mice and had a greater response to exogenous TPO. Furthermore, infection led to higher levels of platelet opsonization and desialylation, both associated with platelet clearance in spleen and liver, respectively. Critically, these changes could be reversed rapidly by drug treatment to reduce parasite load or by administration of TPO agonists. In summary, our findings demonstrate that the mechanisms underpinning thrombocytopenia in EVL are multifactorial and reversible, with no obvious residual damage to the BM microenvironment.

Human visceral leishmaniasis, a parasitic disease of major public health importance in developing countries, is characterized by variable degrees of severity of anemia, but the mechanisms underlying this change in peripheral blood have not been thoroughly explored. Here, we used an experimental model of visceral leishmaniasis in C57BL/6 mice to explore the basis of anemia following infection with Leishmania donovani. 28 days post-infection, mice showed bone marrow dyserythropoiesis by myelogram, with a reduction of TER119⁺ CD71^−/+ erythroblasts. Reduction of medullary erythropoiesis coincided with loss of CD169^high bone marrow stromal macrophages and a reduction of CXCL12-expressing stromal cells. Although the spleen is a site of extramedullary erythropoiesis and erythrophagocytosis, splenectomy did not impact the extent of anemia or affect the repression of medullary hematopoiesis that was observed in infected mice. In contrast, these changes in bone marrow erythropoiesis were not evident in B6.Rag2^−/− mice, but could be fully reconstituted by adoptive transfer of IFNγ-producing but not IFNγ-deficient CD4⁺ T cells, mimicking the expansion of IFNγ-producing CD4⁺ T cells that occurs during infection in wild type mice. Collectively, these data indicate that anemia during experimental murine visceral leishmaniasis can be driven by defects associated with the bone marrow erythropoietic niche, and that this represents a further example of CD4⁺ T cell-mediated immunopathology affecting hematopoietic competence.

Immune thrombocytopenia (ITP) is an acquired autoimmune condition characterized by both reduced platelet production and the destruction of functionally normal platelets by sustained attack from the immune system. However, the effect of prolonged ITP on the more immature hematopoietic progenitors remains an open area of investigation. By using a murine in vivo model of extended ITP, we revealed that ITP progression drives considerable progenitor expansion and bone marrow (BM) remodeling. Single-cell assays using Lin–Sca1+c-Kit+CD48–CD150+ long-term hematopoietic stem cells (LT-HSCs) revealed elevated LT-HSC activation and proliferation in vitro. However, the increased activation did not come at the expense of LT-HSC functionality as measured by in vivo serial transplantations. ITP progression was associated with considerable BM vasodilation and angiogenesis, as well as a twofold increase in the local production of CXCL12, a cytokine essential for LT-HSC function and BM homing expressed at high levels by LepR+ BM stromal cells. This was associated with a 1.5-fold increase in LepR+ BM stromal cells and a 5.5-fold improvement in progenitor homing to the BM. The increase in stromal cells was transient and reverted back to baseline after platelet count returned to normal, but the vasculature changes in the BM persisted. Together, our data demonstrate that LT-HSCs expand in response to ITP and that LT-HSC functionality during sustained hematopoietic stress is maintained through an adapting BM microenvironment.

Atrial fibrillation (AF) is the most frequent atrial arrhythmia. During the last few decades, owing to numerous advancements in the field of electrophysiology, we reached satisfactory outcomes for paroxysmal AF with the help of ablation procedures. But the most challenging type is still persistent AF. The recurrence rate of AF in patients with persistent AF is very high, which shows the inadequacy of pulmonary vein isolation (PVI). Over the last few decades, we have been trying to gain insight into AF mechanisms, and have come to the conclusion that there must be some triggers and substrates other than pulmonary veins. According to many studies, PVI alone is not enough to deal with persistent AF. The purpose of our review is to summarize updates and to clarify the role of coronary sinus (CS) in AF induction and propagation. This review will provide updated knowledge on developmental, histological, and macroscopic anatomical aspects of CS with its role as arrhythmogenic substrate. This review will also inform readers about application of CS in other electrophysiological procedures.

Ly6C^hiinflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6C^himonocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6C^himonocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected withLeishmania donovani, the number of bone marrow Ly6C^himonocytes increased over time. Ly6C^himonocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2^-/-mice <10% of bone marrow monocytes were MHCII⁺at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4⁺T cells. Depletion of CD4⁺T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFNγ produced by CD4⁺T cells. In B6.Il10^-/-mice,L. donovaniinfection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4⁺T cell production of IFNγand resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10^-/-mice and drug (AmBisome^®) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that duringL. donovaniinfection, Ly6C^himonocytes are primed in the bone marrow in a process driven by CD4⁺T cells and whereby IFNγ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.