Fas ligand intracellular signaling: does PSTPIP mediate T cell death?

Fas and Fas ligand (FasL)-induced cell death is critical for the appropriate regulation of immune responses, especially those mediated by T cells. In this letter, several studies are discussed that reinforce the importance of FasL intracellular signaling for CD4 + T cell death, which might involve PSTPIP phosphatase and/or MAPKs.

Evolution of the Major Components of Innate Immunity in Animals.

Innate immunity is present in all animals. In this review, we explore the main conserved mechanisms of recognition and innate immune responses among animals. In this sense, we discuss the receptors, critical for binding to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs); the downstream signaling proteins; and transcription factors that govern immune responses. We also highlight conserved inflammatory mediators that are induced after the recognition of DAMPs and PAMPs. At last, we discuss the mechanisms that are involved in the regulation and/or generation of reactive oxygen species (ROS), influencing immune responses, like heme-oxygenases (HOs).

The dichotomic role of single cytokines: Fine-tuning immune responses.

Cytokines are known for their pleiotropic effects. They can be classified by their function as pro-inflammatory, such as tumor necrosis factor (TNF), interleukin (IL) 1 and IL-12, or anti-inflammatory, like IL-10, IL-35 and transforming growth factor ß (TGF-ß). Though this type of classification is an important simplification for the understanding of the general cytokine's role, it can be misleading. Here, we discuss recent studies that show a dichotomic role of the so-called pro and anti-inflammatory cytokines, highlighting that their function can be dependent on the microenvironment and their concentrations. Furthermore, we discuss how the back-and-forth interplay between cytokines and immunometabolism can influence the dichotomic role of inflammatory responses as an important target to complement cytokine-based therapies.

Mitochondria, Autophagy and Inflammation: Interconnected in Aging.

In this manuscript, I discuss the direct link between abnormalities in inflammatory responses, mitochondrial metabolism and autophagy during the process of aging. It is focused on the cytosolic receptors nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and cyclic GMP-AMP synthase (cGAS); myeloid-derived suppressor cells (MDSCs) expansion and their associated immunosuppressive metabolite, methyl-glyoxal, all of them negatively regulated by mitochondrial autophagy, biogenesis, metabolic pathways and its distinct metabolites.

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. The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the (1) site of tumor development, (2) tumor properties (i. e., tumor metabolism and cytokine receptor expression), and (3) type of immune response that the tumor initially escaped. Therefore, we discuss how low-tolerance organs, such as lungs and brains, might benefit from a less tissue-destructive immune response mediated by Th2 cells. In addition, Th2 cells antitumor effects can be independent of CD8+ T cells, which would circumvent some of the immune escape mechanisms that tumor cells possess, like low expression of major histocompatibility-I (MHC-I). Finally, this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.

Lessons from transmissible cancers for immunotherapy and transplant.

The emergence of horizontal transmission of cancer between vertebrates is an issue that interests scientists and medical society. Transmission requires: (i) a mechanism by which cancer cells can transfer to another organism and (ii) a repressed immune response on the part of the recipient. Transmissible tumors are unique models to comprehend the responses and mechanisms mediated by the major histocompatibility complex (MHC), which can be transposed for transplant biology. Here, we discuss the mechanisms involved in immune-mediated tissue rejection, making a parallel with transmissible cancers. We also discuss cellular and molecular mechanisms involved in cancer immunotherapy and anti-rejection therapies.

The different facets of heme-oxygenase 1 in innate and adaptive immunity.

Heme oxygenase (HO) enzymes are responsible for the main oxidative step in heme degradation, generating equimolar amounts of free iron, biliverdin and carbon monoxide. HO-1 is induced as a crucial stress response protein, playing protective roles in physiologic and pathological conditions, due to its antioxidant, anti-apoptotic and anti-inflammatory effects. The mechanisms behind HO-1-mediated protection are being explored by different studies, affecting cell fate through multiple ways, such as reduction in intracellular levels of heme and ROS, transcriptional regulation, and through its byproducts generation. In this review we focus on the interplay between HO-1 and immune-related signaling pathways, which culminate in the activation of transcription factors important in immune responses and inflammation. We also discuss the dual interaction of HO-1 and inflammatory mediators that govern resolution and tissue damage. We highlight the dichotomy of HO-1 in innate and adaptive immune cells development and activation in different disease contexts. Finally, we address different known anti-inflammatory pharmaceuticals that are now being described to modulate HO-1, and the possible contribution of HO-1 in their anti-inflammatory effects.

Autophagy Modulators in Coronavirus Diseases: A Double Strike in Viral Burden and Inflammation.

Coronaviruses are the etiologic agents of several diseases. Coronaviruses of critical medical importance are characterized by highly inflammatory pathophysiology, involving severe pulmonary impairment and infection of multiple cell types within the body. Here, we discuss the interplay between coronaviruses and autophagy regarding virus life cycle, cell resistance, and inflammation, highlighting distinct mechanisms by which autophagy restrains inflammatory responses, especially those involved in coronavirus pathogenesis. We also address different autophagy modulators available and the rationale for drug repurposing as an attractive adjunctive therapy. We focused on pharmaceuticals being tested in clinical trials with distinct mechanisms but with autophagy as a common target. These autophagy modulators act in cell resistance to virus infection and immunomodulation, providing a double-strike to prevent or treat severe disease development and death from coronaviruses diseases.

Chloroquine inhibits pro-inflammatory effects of heme on macrophages and invivo.

BACKGROUND: Chloroquine has been used successfully to treat Malaria, including by chloroquine-resistant Plasmodium sp., indicating that it has effects on disease itself. Since heme has inflammatory effects and contributes to the pathogenesis of hemolytic diseases, we hypothesize that the anti-inflammatory effect of chloroquine is partially due to its inhibitory effect on heme-induced macrophage activation and on inflammatory tissue damage. METHODS: Bone marrow derived macrophages (BMDMs) were incubated with chloroquine before stimulation with heme, in different conditions, to evaluate cytokines secretion, ROS production, mitogen activated protein kinases (MAPK) or spleen tyrosine kinase (Syk) activation, alone or combined with LPS. The effects of chloroquine upon heme inflammation were also evaluated in vivo, through simultaneous i.p. injection of LPS and heme, intratracheal instillation of Poly-IC followed by heme injection, and in a rhabdomyolysis model. RESULTS: Chloroquine inhibited TNF secretion, mitochondrial ROS production, MAPK, and Syk activation induced by heme. Inhibition of TNF production could be mimicked by zinc ionophore quercetin, but not by primaquine, a chloroquine analog with low affinity for heme. IL-6 and IL-1ß secretions induced by heme in the presence of PRRs agonists were inhibited by chloroquine, but not by calcium chelator BAPTA or inhibitor of endosomal acidification concamycin B. Chloroquine also protected mice from heme inflammatory effects in vivo, inhibiting lethal synergism with PRR agonists, lung pathology caused by heme injection after intratracheal instillation of Poly-IC, and delaying death after rhabdomyolisis. CONCLUSION: Our data indicate that chloroquine might be used as a supportive therapy to control heme-induced deleterious inflammation in different hemolytic diseases.