http://nizetlab.ucsd.edu/Publications/HIF-Immunity.pdf

HIF Transcription Factors, Inflammation, and Immunity

Alternatively activated microglia and macrophages in the central nervous system.

The biphasic function of microglia in ischemic stroke.

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease.

* Abbreviation
 : EAE
 : experimental autoimmune encephalomyelitis
 LPS
 : lipopolysaccharide
 PET
 : positron emission tomography

/pdf/roles-of-microglia-in-brain-development-tissue-maintenance-4kwwaua97h.pdf

Roles of microglia in brain development, tissue maintenance and repair

MicroRNAs (miRNAs) are a class of small (∼22 nucleotides) noncoding RNAs involved in the regulation of gene expression at the post-translational level. It is estimated that 30-90% of human genes are regulated by miRNAs, which makes these molecules of great importance for cell growth, activation, and differentiation. Microglia is CNS-resident cells of a myeloid lineage that play an important role in immune surveillance and are actively involved in many neurologic pathologies. Although the exact origin of microglia remains enigmatic, it is established that primitive macrophages from a yolk sac populate the brain and spinal cord in normal conditions throughout development. During various pathological events such as neuroinflammation, bone marrow derived myeloid cells also migrate into the CNS. Within the CNS, both primitive macrophages from the yolk sac and bone marrow derived myeloid cells acquire a specific phenotype upon interaction with other cell types within the CNS microenvironment. The factors that drive differentiation of progenitors into microglia and control the state of activation of microglia and bone marrow-derived myeloid cells within the CNS are not well understood. In this review we will summarize the role of miRNAs during activation and differentiation of myeloid cells. The role of miR-124 in the adaptation of microglia and macrophages to the CNS microenvironment will be further discussed. We will also summarize the role of miRNAs as modulators of activation of microglia and microphages. Finally, we will describe the role of miR-155 and miR-124 in the polarization of macrophages towards classically and alternatively activated phenotypes.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.22363

MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS

MicroRNA-mediated regulation of gene expression appears to be involved in a variety of cellular processes, including development, differentiation, proliferation, and apoptosis. Mir-146a is thought to be involved in the regulation of the innate immune response, and its expression is increased in tissues associated with chronic inflammation. Among the predicted gene targets for mir-146a, the chemokine CCL8/MCP-2 is a ligand for the CCR5 chemokine receptor and a potent inhibitor of CD4/CCR5-mediated HIV-1 entry and replication. In the present study, we have analyzed changes in the expression of mir-146a in primary human fetal microglial cells upon infection with HIV-1 and found increased expression of mir-146a. We further show that CCL8/MCP-2 is a target for mir-146a in HIV-1 infected microglia, as overexpression of mir-146a prevented HIV-induced secretion of MCP-2 chemokine. The clinical relevance of our findings was evaluated in HIV-encephalitis (HIVE) brain samples in which decreased levels of MCP-2 and increased levels of mir-146a were observed, suggesting a role for mir-146a in the maintenance of HIV-mediated chronic inflammation of the brain.

CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

HIV-1 Vpr deregulates calcium secretion in neural cells

Particularly interesting new cysteine- histidine- rich protein (PINCH) is an adaptor protein that our data have shown is required for neurite extension under stressful conditions. Our previous studies also report that PINCH is recalled by neurons showing decreased levels of synaptodendritic signaling proteins such as MAP2 or synaptophysin in the brains of human immunodeficiency virus (HIV) patients. The current study addressed potential role(s) for PINCH in neurodegenerative diseases. Mass spectrometry predicted the interaction of PINCH with Tau and with members of the heat shock response. Our in vitro data confirmed that PINCH binds to hyperphosphorylated (hp) Tau and to E3 ubiquitin ligase, carboxy-terminus of heat shock-70 interacting protein. Silencing PINCH prior to induction of hp-Tau resulted in more efficient clearance of accumulating hp-Tau, suggesting that PINCH may play a role in stabilizing hp-Tau. Accumulation of hp-Tau is implicated in more than 20 neuropathological diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD), and human immunodeficiency virus encephalitis (HIVE). Analyses of brain tissues from HIVE, AD and FTD patients showed that PINCH is increased and binds to hp-Tau. These studies address a new mechanism by which AD and HIV may intersect and identify PINCH as a contributing factor to the accumulation of hyperphosphorylated Tau.

PINCH in the cellular stress response to tau-hyperphosphorylation.

Infection with HIV-1 induces a variety of biological alterations to the host that are beneficial to the life cycle of the virus but may have adverse effects on the host cell Here we demonstrate that expression of Rad51, a major component of the homologous recombination-directed DNA repair (HRR) pathway, is induced upon HIV-1 infection of microglial cells Activation of Rad51 expression positively impacts on HIV-1 LTR transcription through a region of the viral promoter known for binding the inducible transcription factor NFκB Rad51 showed the ability to form a complex with the p65 subunit of NFκB and regulate the level of p65 interaction with LTR DNA encompassing the κB motif This study provides evidence for reciprocal interaction of HIV-1 and a host DNA repair protein that impacts on expression of the viral genome These results also point to the ability of HIV-1 to recruit proteins involved in DNA repair that are necessary for retroviral DNA integration, efficient replication and prevention of viral-induced cell death

Inna Rom

Papers

CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

HIV-1 Vpr deregulates calcium secretion in neural cells

PINCH in the cellular stress response to tau-hyperphosphorylation.

Activation of HIV-1 LTR by Rad51 in microglial cells.