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 in vivo 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. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

Immune Responses in Leishmaniasis: An Overview.

Leishmaniasis is a parasitic, widespread, and neglected disease that affects more than 90 countries in the world. More than 20 Leishmania species cause different forms of leishmaniasis that range in severity from cutaneous lesions to systemic infection. The diversity of leishmaniasis forms is due to the species of parasite, vector, environmental and social factors, genetic background, nutritional status, as well as immunocompetence of the host. Here, we discuss the role of the immune system, its molecules, and responses in the establishment, development, and outcome of Leishmaniasis, focusing on innate immune cells and Leishmania major interactions.

The Sweet Side of Fungal Infections: Structural Glycan Diversity and Its Importance for Pathogenic Adaptation.

Fungal infections are the most common secondary infections in debilitated individuals in a state of chronic disease or immunosuppression. Despite this, most fungal infections are neglected, mainly due to the lower frequency of their more severe clinical forms in immunocompetent individuals with a healthy background. However, over the past few years, several cases of severe fungal infections in healthy individuals have provoked a change in the epidemiological dynamics of fungal infections around the world, both due to recurrent outbreaks in previously infrequent regions and the greater emergence of more pathogenic fungal variants affecting healthy individuals, such as in the Cryptococcus genus. Therefore, before the arrival of a scenario of prevalent severe fungal infections, it is necessary to assess more carefully what are the real reasons for the increased incidence of fungal infection globally. What are the factors that are currently contributing to this new possible epidemiological dynamic? Could these be of a structural nature? Herein, we propose a discussion based on the importance of the virulence factors of glycoconjugate composition in the adaptation of pathogenic fungal species into the current scenario of increasing severity of these infections.

Human Kinetoplastid Protozoan Infections: Where Are We Going Next?

Kinetoplastida trypanosomatidae microorganisms are protozoan parasites exhibiting a developmental stage in the gut of insect vectors and tissues of vertebrate hosts. During the vertebrate infective stages, these parasites alter the differential expression of virulence genes, modifying their biological and antigenic properties in order to subvert the host protective immune responses and establish a persistent infection. One of the hallmarks of kinetoplastid parasites is their evasion mechanisms from host immunity, leading to disease chronification. The diseases caused by kinetoplastid parasites are neglected by the global expenditures in research and development, affecting millions of individuals in the low and middle-income countries located mainly in the tropical and subtropical regions. However, investments made by public and private initiatives have over the past decade leveraged important lines of intervention that if well-integrated to health care programs will likely accelerate disease control initiatives. This review summarizes recent advances in public health care principles, including new drug discoveries and their rational use with chemotherapeutic vaccines, and the implementation of control efforts to spatially mapping the kinetoplastid infections through monitoring of infected individuals in epidemic areas. These approaches should bring us the means to track genetic variation of parasites and drug resistance, integrating this knowledge into effective stewardship programs to prevent vector-borne kinetoplastid infections in areas at risk of disease spreading.

Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses.

The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege.

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. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses.