Differential regulation of lung homeostasis and silicosis by the TAM receptors MerTk and Axl.

Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma.

Immunopathogenesis in infection: a role for suppressed macrophages and apoptotic cells.

During infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease.

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection.

Adaptive immunity controls Trypanosoma cruzi infection, but the protozoan parasite persists and causes Chagas disease. T cells undergo apoptosis, and the efferocytosis of apoptotic cells might suppress macrophages and exacerbate parasite infection. Nonetheless, the receptors involved in the efferocytosis of apoptotic lymphocytes during infection remain unknow.

Distinct T helper cell-mediated antitumor immunity: T helper 2 cells in focus.

The adaptive arm of the immune system is crucial for appropriate antitumor immune responses. It is generally accepted that clusters of differentiation 4 (CD4) T cells, which mediate T helper (Th) 1 immunity (type 1 immunity), are the primary Th cell subtype associated with tumor elimination. In this review, we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans, with a focus on Th2 cells.

New Therapeutic Tools to Shape Monocyte Functional Phenotypes in Leishmaniasis.

In the innate immunity to infection tissue-resident macrophages and inflammatory monocytes accumulate host-cell, effector, and efferocytosis functions. In addition, neutrophils, as host, effector, and apoptotic cells, as well as tissue-resident and monocyte-derived dendritic cells (DCs) imprint innate and adaptive immunity to parasites. Macrophages develop phenotypes ranging from antimicrobial M1 to parasite-permissive M2, depending on mouse strain, species, and T-cell cytokines.

RANK Ligand Helps Immunity to by Skewing M2-Like Into M1 Macrophages.

Macrophages host infection, which causes cutaneous Leishmaniasis in humans. In the murine model, resistance to infection depends on the host immunity mediated by CD4 T-cell cytokines and macrophages. In association to other stimuli, the Th1 cytokine IFN-γ induces NO-mediated microbial killing by M1/classically-activated macrophages.

Infection Induces Cellular Stress Response and Senescence-Like Phenotype in Murine Fibroblasts.

infects and replicates within a wide variety of immune and non-immune cells. Here, we investigated early cellular responses induced in NIH-3T3 fibroblasts upon infection with trypomastigote forms of . We show that fibroblasts were susceptible to infection and started to release trypomastigotes to the culture medium after 4 days of infection.

Antibody Repertoires Identify β-Tubulin as a Host Protective Parasite Antigen in Mice Infected With .

Few studies investigate the major protein antigens targeted by the antibody diversity of infected mice with . To detect global IgG antibody specificities, sera from infected mice were immunoblotted against whole extracts. By proteomic analysis, we were able to identify the most immunogenic proteins.

All- Retinoic Acid Promotes an M1- to M2-Phenotype Shift and Inhibits Macrophage-Mediated Immunity to .

As key cells, able to host and kill parasites, inflammatory monocytes/macrophages are potential vaccine and therapeutic targets to improve immune responses in Leishmaniasis. Macrophage phenotypes range from M1, which express NO-mediated microbial killing, to M2 macrophages that might help infection. Resistance to Leishmaniasis depends on species, mouse strain, and both innate and adaptive immunity.

Epigenetic Control of Macrophage Shape Transition towards an Atypical Elongated Phenotype by Histone Deacetylase Activity.

Inflammatory chronic pathologies are complex processes characterized by an imbalance between the resolution of the inflammatory phase and the establishment of tissue repair. The main players in these inflammatory pathologies are bone marrow derived monocytes (BMDMs). However, how monocyte differentiation is modulated to give rise to specific macrophage subpopulations (M1 or M2) that may either maintain the chronic inflammatory process or lead to wound healing is still unclear.

Innate immunity to Leishmania infection: within phagocytes.

Infection by Leishmania takes place in the context of inflammation and tissue repair. Besides tissue resident macrophages, inflammatory macrophages and neutrophils are recruited to the infection site and serve both as host cells and as effectors against infection. Recent studies suggest additional important roles for monocytes and dendritic cells.

Infection with Leishmania major induces a cellular stress response in macrophages.

We investigated early cellular responses induced by infection with Leishmania major in macrophages from resistant C57/BL6 mice. Infection increased production of reactive oxygen species by resident, but not inflammatory peritoneal macrophages. In addition, infection increased activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) in resident, but not in inflammatory peritoneal macrophages.

Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection.

We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-γ and IL-4 cytokine responses to L. major antigens.

Pathogen-induced proapoptotic phenotype and high CD95 (Fas) expression accompany a suboptimal CD8+ T-cell response: reversal by adenoviral vaccine.

MHC class Ia-restricted CD8(+) T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8(+) T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8(+) T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal.

Myeloid-derived suppressor cells help protective immunity to Leishmania major infection despite suppressed T cell responses.

Th1/Th2 cytokines play a key role in immune responses to Leishmania major by controlling macrophage activation for NO production and parasite killing. MDSCs, including myeloid precursors and immature monocytes, produce NO and suppress T cell responses in tumor immunity. We hypothesized that NO-producing MDSCs could help immunity to L.

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF-alpha secretion and reduce parasite replication in macrophages.

Phagocytic removal of apoptotic lymphocytes exacerbates replication of Trypanosoma cruzi in macrophages. We investigated the presence of Ab against apoptotic lymphocytes in T. cruzi infection and the role of these Ab in parasite replication.

The importance of apoptosis for immune regulation in Chagas disease.

Host cell apoptosis plays an important immune regulatory role in parasitic infections. Infection of mice with Trypanosoma cruzi, the causative agent of Chagas disease, induces lymphocyte apoptosis. In addition, phagocytosis of apoptotic cells stimulates the growth of T.

Targeting caspases in intracellular protozoan infections.

Caspases are cysteine aspartases acting either as initiators (caspases 8, 9, and 10) or executioners (caspases 3, 6, and 7) to induce programmed cell death by apoptosis. Parasite infections by certain intracellular protozoans increase host cell life span by targeting caspase activation. Conversely, caspase activation, followed by apoptosis of lymphocytes and other cells, prevents effective immune responses to chronic parasite infection.

Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection.

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following T cell activation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells.

Apoptosis differentially regulates mesenteric and subcutaneous lymph node immune responses to Trypanosoma cruzi.

Infection with Trypanosoma cruzi causes expansion of subcutaneous (SLN) and atrophy of mesenteric (MLN) lymph nodes. Here we show that excision of MLN increased parasitemia in T. cruzi-infected mice.

Neutrophils activate macrophages for intracellular killing of Leishmania major through recruitment of TLR4 by neutrophil elastase.

We investigated the role of neutrophil elastase (NE) in interactions between murine inflammatory neutrophils and macrophages infected with the parasite Leishmania major. A blocker peptide specific for NE prevented the neutrophils from inducing microbicidal activity in macrophages. Inflammatory neutrophils from mutant pallid mice were defective in the spontaneous release of NE, failed to induce microbicidal activity in wild-type macrophages, and failed to reduce parasite loads upon transfer in vivo.

Decoding caspase signaling in host immunity to the protozoan Trypanosoma cruzi.

Caspases, a family of cysteinyl-aspartate-specific proteases, induce apoptosis but are also involved in signal transduction in live cells. Caspase activation and apoptosis in T lymphocytes occur following infection with parasites and might affect immune responses. Rapid progress has occurred in the development and testing of caspase inhibitors and other apoptosis blockers, which are potentially useful for treating diseases associated with the pathogenic effects of apoptosis.

Cross-talk between apoptosis and cytokines in the regulation of parasitic infection.

Parasitic diseases have worldwide medical and economical impact. Host T lymphocytes and the cytokines they produce determine the outcome of parasitic infections. Programmed cell death by apoptosis is induced in the course of parasitic infections, and affects cytokine production by removing activated effector T and B cells.