Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden.

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden.

Integrin α3 promotes T17 cell polarization and extravasation during autoimmune neuroinflammation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including T17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic T17 cell migration. Here, we report integrin α3 as a T17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis.

20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment.

Microglia C-lectin/selectin' neurons to eat.

β-glucosylceramide (β-GlcCer) accumulates in Gaucher disease, but how β-GlcCer, a Mincle ligand, causes characteristic neuroinflammation and neuronopathy is poorly understood. In this issue of Immunity, Shimizu et al. reveal that Mincle-dependent activation of microglia led to phagocytosis of neurons and neurologic symptoms.

Osteopontin (OPN)/SPP1: from its biochemistry to biological functions in the innate immune system and the central nervous system (CNS).

Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions caused by infections, allergic responses, autoimmunity and tissue damage. Many cell types in the peripheral immune system express OPN with various functions, which could be beneficial or detrimental.

Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection thymocytes.

Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRβ chains in DN3 thymocytes, which promotes the transition of DN4 cells to the DP stage. The signals driving the expansion of DN2 thymocytes are well studied.

Infection and inflammation: New perspectives on Alzheimer's disease.

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: "Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD).

Dectin-1 signaling in neutrophils up-regulates PD-L1 and triggers ROS-mediated suppression of CD4 T cells.

Dectin-1 is known to drive proinflammatory cytokine production by macrophages and dendritic cells which promotes Th17 CD4 T cell responses in the setting of fungal infection. However, the role of Dectin-1 signaling in neutrophils and its impact on CD4 T cells is not well understood. In this study, we found that neutrophils stimulated with a Dectin-1 agonist diminish CD4 T cell viability in a rapid and reactive oxygen species (ROS)-dependent manner.

Host immune responses in the central nervous system during fungal infections.

Fungal infections in the central nervous system (CNS) cause high morbidity and mortality. The frequency of CNS mycosis has increased over the last two decades as more individuals go through immunocompromised conditions for various reasons. Nevertheless, options for clinical interventions for CNS mycoses are still limited.

Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome.

Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remains unknown.

The AIM2 inflammasome is activated in astrocytes during the late phase of EAE.

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune conditions influenced by inflammasomes.

Secreted osteopontin from CD4 T cells limits acute graft-versus-host disease.

Osteopontin (OPN) has been considered a potential biomarker of graft-versus-host disease (GVHD). However, the function of OPN in GVHD is still elusive. Using a mouse model of acute GVHD (aGVHD), we report that OPN generated by CD4 T cells is sufficient to exert a beneficial effect in controlling aGVHD through limiting gastrointestinal pathology, a major target organ of aGVHD.

Emerging roles of Dectin-1 in noninfectious settings and in the CNS.

Dectin-1 is a C-type lectin receptor (CLR) expressed on the surface of various mammalian myeloid cells. Dectin-1 recognizes β-glucans and elicits antifungal proinflammatory immune responses. Recent studies have begun to examine the biology of Dectin-1 in previously less explored settings, such as homeostasis, sterile inflammation, and in the central nervous system.

Targeting Inflammasomes to Treat Neurological Diseases.

Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis.

Single-Cell Transcriptional Heterogeneity of Neutrophils During Acute Pulmonary Infection.

Neutrophils are critical as the first-line defense against fungal pathogens. Yet, previous studies indicate that neutrophil function is complex during infection. To better understand the role of neutrophils in acute pulmonary cryptococcosis, we analyzed neutrophil heterogeneity by single-cell transcriptional analysis of immune cells in the lung of -infected mice from a published dataset.

Dectin-1 limits autoimmune neuroinflammation and promotes myeloid cell-astrocyte crosstalk via Card9-independent expression of Oncostatin M.

Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease.

Th1-Dependent -Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage.

-associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of (). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with serotype A strain H99, which is highly virulent and the most intensively studied.

Functional heterogeneity of alveolar macrophage population based on expression of CXCL2.

Alveolar macrophages (AMs) are the major lung-resident macrophages and have contradictory functions. AMs maintain tolerance and tissue homeostasis, but they also initiate strong inflammatory responses. However, such opposing roles within the AM population were not known to be simultaneously generated and coexist.

Core -Glycan Structures Are Critical for the Pathogenicity of Cryptococcus neoformans by Modulating Host Cell Death.

is a human-pathogenic fungal pathogen that causes life-threatening meningoencephalitis in immunocompromised individuals. To investigate the roles of -glycan core structure in cryptococcal pathogenicity, we constructed mutant strains of with defects in the assembly of lipid-linked -glycans in the luminal side of the endoplasmic reticulum (ER). Deletion of (Δ), which encodes dolichyl-phosphate-mannose (Dol-P-Man)-dependent α-1,3-mannosyltransferase, resulted in the production of truncated neutral -glycans carrying five mannose residues as a major species.

Yolk-sac-derived macrophages progressively expand in the mouse kidney with age.

Renal macrophages represent a highly heterogeneous and specialized population of myeloid cells with mixed developmental origins from the yolk-sac and hematopoietic stem cells (HSC). They promote both injury and repair by regulating inflammation, angiogenesis, and tissue remodeling. Recent reports highlight differential roles for ontogenically distinct renal macrophage populations in disease.