APE1 is a master regulator of the ATR-/ATM-mediated DNA damage response.

To maintain genomic integrity, cells have evolved several conserved DNA damage response (DDR) pathways in response to DNA damage and stress conditions. Apurinic/apyrimidinic endonuclease 1 (APE1) exhibits AP endonuclease, 3'-5' exonuclease, 3'-phosphodiesterase, and 3'-exoribonuclease activities and plays critical roles in the DNA repair and redox regulation of transcription. However, it remains unclear whether and how APE1 is involved in DDR pathways.

Immunostimulatory nucleic acid nanoparticles (NANPs) augment protective osteoblast and osteoclast type I interferon responses to Staphylococcus aureus.

Recalcitrant staphylococcal osteomyelitis may be due, in part, to the ability of Staphylococcus aureus to invade bone cells. However, osteoclasts and osteoblasts are now recognized to shape host responses to bacterial infection and we have recently described their ability to produce IFN-β following S. aureus infection and limit intracellular bacterial survival/propagation.

cGAS Mediates the Inflammatory Responses of Human Microglial Cells to Genotoxic DNA Damage.

Genomic instability is a key driving force for the development and progression of many age-related neurodegenerative diseases and central nervous system (CNS) cancers. Recently, the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), has been shown to detect and respond to self-DNA accumulation resulting from DNA damaging insults in peripheral cell types. cGAS has been shown to be important in the responses of microglia to DNA viruses and amyloid beta, and we have reported that it underlies the responses of human microglia to exogenous DNA.

Cytosolic DNA sensors and glial responses to endogenous DNA.

Genomic instability is a key driving force for the development and progression of many neurodegenerative diseases and central nervous system (CNS) cancers. The initiation of DNA damage responses is a critical step in maintaining genomic integrity and preventing such diseases. However, the absence of these responses or their inability to repair genomic or mitochondrial DNA damage resulting from insults, including ionizing radiation or oxidative stress, can lead to an accumulation of self-DNA in the cytoplasm.

Staphylococcus aureus Infection Induces the Production of the Neutrophil Chemoattractants CXCL1, CXCL2, CXCL3, CXCL5, CCL3, and CCL7 by Murine Osteoblasts.

Staphylococcus aureus is the principal causative agent of osteomyelitis, a serious bacterial infection of bone that is associated with progressive inflammatory damage. Bone-forming osteoblasts have increasingly been recognized to play an important role in the initiation and progression of detrimental inflammation at sites of infection and have been demonstrated to release an array of inflammatory mediators and factors that promote osteoclastogenesis and leukocyte recruitment following bacterial challenge. In the present study, we describe elevated bone tissue levels of the potent neutrophil-attracting chemokines CXCL1, CXCL2, CXCL3, CXCL5, CCL3, and CCL7 in a murine model of posttraumatic staphylococcal osteomyelitis.

Therapeutic immunomodulation by rationally designed nucleic acids and nucleic acid nanoparticles.

The immune system has evolved to defend organisms against exogenous threats such as viruses, bacteria, fungi, and parasites by distinguishing between "self" and "non-self". In addition, it guards us against other diseases, such as cancer, by detecting and responding to transformed and senescent cells. However, for survival and propagation, the altered cells and invading pathogens often employ a wide range of mechanisms to avoid, inhibit, or manipulate the immunorecognition.

Induction of protective interferon-β responses in murine osteoblasts following infection.

Introduction: The refractory and recurrent nature of chronic staphylococcal osteomyelitis may be due, at least in part, to the ability of to invade and persist within bone-forming osteoblasts. However, osteoblasts are now recognized to respond to . infection and produce numerous immune mediators and bone regulatory factors that can shape the host response.

Substance P Exacerbates the Inflammatory and Pro-osteoclastogenic Responses of Murine Osteoclasts and Osteoblasts to Staphylococcus aureus.

Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S. aureus and produce an array of inflammatory and pro-osteoclastogenic mediators, thereby contributing to such damage.

Z-DNA binding protein 1 mediates necroptotic and apoptotic cell death pathways in murine astrocytes following herpes simplex virus-1 infection.

Background: The mechanisms by which glia respond to viral central nervous system (CNS) pathogens are now becoming apparent with the demonstration that microglia and astrocytes express an array of pattern recognition receptors that include intracellular RNA and DNA sensors. We have previously demonstrated that glia express Z-DNA binding protein 1 (ZBP1) and showed that this cytosolic nucleic acid sensor contributes to the inflammatory/neurotoxic responses of these cells to herpes simplex virus-1 (HSV-1). However, the relative contribution made by ZBP1- to HSV-1-mediated cell death in glia has not been determined.

The immunorecognition, subcellular compartmentalization, and physicochemical properties of nucleic acid nanoparticles can be controlled by composition modification.

Nucleic acid nanoparticles (NANPs) have become powerful new platforms as therapeutic and diagnostic tools due to the innate biological ability of nucleic acids to identify target molecules or silence genes involved in disease pathways. However, the clinical application of NANPs has been limited by factors such as chemical instability, inefficient intracellular delivery, and the triggering of detrimental inflammatory responses following innate immune recognition of nucleic acids. Here, we have studied the effects of altering the chemical composition of a circumscribed panel of NANPs that share the same connectivity, shape, size, charge and sequences.

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens.

Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood.

The intracellular DNA sensors cGAS and IFI16 do not mediate effective antiviral immune responses to HSV-1 in human microglial cells.

Glia play a key role in immunosurveillance within the central nervous system (CNS) and can recognize a wide range of pathogen-associated molecular patterns (PAMPS) via members of multiple pattern recognition receptor (PRR) families. Of these, the expression of cytosolic/nuclear RNA and DNA sensors by glial cells is of particular interest as their ability to interact with intracellular nucleic acids suggests a critical role in the detection of viral pathogens. The recently discovered DNA sensors cyclic GMP-AMP synthase (cGAS) and interferon gamma-inducible protein 16 (IFI16) have been reported to be important for the recognition of DNA pathogens such as herpes simplex virus-1 (HSV-1) in peripheral human cell types, and we have recently demonstrated that human glia express cGAS and its downstream adaptor molecule stimulator of interferon genes (STING).

Retinoic acid inducible gene-I mediated detection of bacterial nucleic acids in human microglial cells.

Background: Bacterial meningitis and meningoencephalitis are associated with devastating neuroinflammation. We and others have demonstrated the importance of glial cells in the initiation of immune responses to pathogens invading the central nervous system (CNS). These cells use a variety of pattern recognition receptors (PRRs) to identify common pathogen motifs and the cytosolic sensor retinoic acid inducible gene-1 (RIG-I) is known to serve as a viral PRR and initiator of interferon (IFN) responses.

A cationic amphiphilic co-polymer as a carrier of nucleic acid nanoparticles (Nanps) for controlled gene silencing, immunostimulation, and biodistribution.

Programmable nucleic acid nanoparticles (NANPs) provide controlled coordination of therapeutic nucleic acids (TNAs) and other biological functionalities. Beyond multivalence, recent reports demonstrate that NANP technology can also elicit a specific immune response, adding another layer of customizability to this innovative approach. While the delivery of nucleic acids remains a challenge, new carriers are introduced and tested continuously.

Murine astrocytes are responsive to the pro-inflammatory effects of IL-20.

Glia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma. We have previously demonstrated the ability of activated astrocytes to rapidly produce pro-inflammatory mediators followed by a transition to an anti-inflammatory cytokine production profile that includes the immunosuppressive cytokine interleukin (IL)-10 and the closely related cytokines IL-19 and IL-24. IL-20, another member of the IL-10 family, is known to modulate immune cell activity in the periphery and we have previously demonstrated that astrocytes constitutively express the cognate receptors for this cytokine.

Murine astrocytes produce IL-24 and are susceptible to the immunosuppressive effects of this cytokine.

Background: Glia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma. We have previously demonstrated the ability of activated glia to rapidly produce pro-inflammatory mediators followed by a transition to an anti-inflammatory cytokine production profile that includes the immunosuppressive cytokine interleukin (IL)-10 and the closely related cytokine IL-19. IL-24, another member of the IL-10 family, has been studied in a number of inflammatory conditions in the periphery and is known to modulate immune cell activity.

The Interleukin-10 Family of Cytokines and Their Role in the CNS.

Resident cells of the central nervous system (CNS) play an important role in detecting insults and initiating protective or sometimes detrimental host immunity. At peripheral sites, immune responses follow a biphasic course with the rapid, but transient, production of inflammatory mediators giving way to the delayed release of factors that promote resolution and repair. Within the CNS, it is well known that glial cells contribute to the onset and progression of neuroinflammation, but it is only now becoming apparent that microglia and astrocytes also play an important role in producing and responding to immunosuppressive factors that serve to limit the detrimental effects of such responses.

Elucidating the Interactive Roles of Glia in Alzheimer's Disease Using Established and Newly Developed Experimental Models.

Alzheimer's disease (AD) is an irreversible neurodegenerative illness and the exact etiology of the disease remains unknown. It is characterized by long preclinical and prodromal phases with pathological features including an accumulation of amyloid-beta (Aβ) peptides into extracellular Aβ plaques in the brain parenchyma and the formation of intracellular neurofibrillary tangles (NFTs) within neurons as a result of abnormal phosphorylation of microtubule-associated tau proteins. In addition, prominent activation of innate immune cells is also observed and/or followed by marked neuroinflammation.

A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyperactivation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform.

Human microglia and astrocytes constitutively express the neurokinin-1 receptor and functionally respond to substance P.

Background: The tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes. More recently, SP/NK-1R interactions have been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis.