Microglia in the Brain Tumor Microenvironment.

Microglia are the brain resident phagocytes that act as the primary form of the immune defense in the central nervous system. These cells originate from primitive macrophages that arise from the yolk sac. Advances in imaging and single-cell RNA-seq technologies provided new insights into the complexity of microglia biology.Microglia play an essential role in the brain development and maintenance of brain homeostasis. They are also crucial in injury repair in the central nervous system. The tumor microenvironment is complex and includes neoplastic cells as well as varieties of host and infiltrating immune cells. Microglia are part of the glioma microenvironment and play a critical part in initiating and maintaining tumor growth and spread. Microglia can also act as effector cells in treatments against gliomas. In this chapter, we summarize the current knowledge of how and where microglia are generated. We also discuss their functions during brain development, injury repair, and homeostasis. Moreover, we discuss the role of microglia in the tumor microenvironment of gliomas and highlight their therapeutic implications.

Francisella DnaK inhibits tissue-nonspecific alkaline phosphatase.

Following pulmonary infection with Francisella tularensis, we observed an unexpected but significant reduction of alkaline phosphatase, an enzyme normally up-regulated following inflammation. However, no reduction was observed in mice infected with a closely related gram-negative pneumonic organism (Klebsiella pneumoniae) suggesting the inhibition may be Francisella-specific. In similar fashion to in vivo observations, addition of Francisella lysate to exogenous alkaline phosphatase (tissue-nonspecific isozyme) was inhibitory. Partial purification and subsequent proteomic analysis indicated the inhibitory factor to be the heat shock protein DnaK. Incubation with increasing amounts of anti-DnaK antibody reduced the inhibitory effect in a dose-dependent manner. Furthermore, DnaK contains an adenosine triphosphate binding domain at its N terminus, and addition of adenosine triphosphate enhances dissociation of DnaK with its target protein, e.g. alkaline phosphatase. Addition of adenosine triphosphate resulted in decreased DnaK co-immunoprecipitated with alkaline phosphatase as well as reduction of Francisella-mediated alkaline phosphatase inhibition further supporting the binding of Francisella DnaK to alkaline phosphatase. Release of DnaK via secretion and/or bacterial cell lysis into the extracellular milieu and inhibition of plasma alkaline phosphatase could promote an orchestrated, inflammatory response advantageous to Francisella.