An immunocompetent human kidney on-a-chip model to study renal inflammation and immune-mediated injury.

Kidney damage and dysfunction is an emerging health issue worldwide resulting in high morbidity and mortality rates. Numerous renal diseases are recognized to be driven by the immune system. Despite this recognition, the development of targeted therapies has been challenging as knowledge of the underlying mechanism and complex interactions remains insufficient.

Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge.

SCARF1-Induced Efferocytosis Plays an Immunomodulatory Role in Humans, and Autoantibodies Targeting SCARF1 Are Produced in Patients with Systemic Lupus Erythematosus.

Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE.

Linking indirect effects of cytomegalovirus in transplantation to modulation of monocyte innate immune function.

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed to immune modulation by CMV, including increased mortality from fungal disease, allograft dysfunction and rejection in solid organ transplantation, and graft-versus-host-disease in stem cell transplantation. Monocytes, key cellular targets of CMV, are permissive to primary, latent and reactivated CMV infection.

Immune correlates of tuberculosis disease and risk translate across species.

One quarter of the world's population is infected with (), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery.

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location.

Redirection to the bone marrow improves T cell persistence and antitumor functions.

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy.

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140.

Epigenetic "readers" that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)-containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SNPs have remained unclear.

A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature.

Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys.

Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys.

Characterization of the early local immune response to Ixodes ricinus tick bites in human skin.

Little is known about the immunomodulation by tick saliva during a natural tick bite in human skin, the site of the tick-host interaction. We examined the expression of chemokines, cytokines and leucocyte markers on the mRNA levels and histopathologic changes in human skin biopsies of tick bites (n=37) compared to unaffected skin (n=9). Early tick-bite skin lesions (<24 hours of tick attachment) were characterized by a predominance of macrophages and dendritic cells, elevated mRNA levels of macrophage chemoattractants (CCL2, CCL3, CCL4) and neutrophil chemoattractants (CXCL1, CXCL8), of the pro-inflammatory cytokine, IL-1β, and the anti-inflammatory cytokine, IL-5.

Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes.

Unlabelled: Multiple EGF-like domains 10 (Megf10) is a class F scavenger receptor (SR-F3) expressed on astrocytes and myosatellite cells, and recessive mutations in humans result in early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Here we report that Megf10-deficient mice have increased apoptotic cells in the developing cerebellum and have impaired phagocytosis of apoptotic cells by astrocytes ex vivo We also report that cells transfected with Megf10 gain the ability to phagocytose apoptotic neurons and that Megf10 binds with high affinity to C1q, an eat-me signal for apoptotic cells. In contrast, cells expressing Megf10 with EMARDD mutations have impaired apoptotic cell clearance and impaired binding to C1q.

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.

CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling.

Depletion of CD11c⁺ cells in the CD11c.DTR model drives expansion of unique CD64⁺ Ly6C⁺ monocytes that are poised to release TNF-α.

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated.

The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity.

The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4(-/-) mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7.

AGS, SLE, and RNASEH2 mutations: translating insights into therapeutic advances.

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by the presence of nucleic acid- and protein-targeting autoantibodies and an aberrant type I IFN expression signature. Aicardi-Goutières syndrome (AGS) is an autosomal-recessive encephalopathy in children that is characterized by mutations in numerous nucleic acid repair enzymes and elevated IFN levels. Phenotypically, patients with AGS and SLE share many similarities.

Standardizing scavenger receptor nomenclature.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a variety of ligands, including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature.

The microglial sensome revealed by direct RNA sequencing.

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice.

The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity.

The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells.

Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression.

In Alzheimer's disease, soluble amyloid-β causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-β are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-β expressed on myeloid cells.

The role of dendritic cells in the innate recognition of pathogenic fungi (A. fumigatus, C. neoformans and C. albicans).

Dendritic cells (DCs) are the bridge between the innate and adaptive immune system. DCs are responsible for sensing and patrolling the environment, initiating a host response and instructing the proper adaptive immune response against pathogens. Recent advances in medical treatments have led to increased use of immunosuppressive drugs, leading to the emergence of fungal species that cause life-threatening infections in humans.

Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin.

Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury.

Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid-immunoglobulin complexes in humans.

Donor lymphocyte infusion (DLI), whereby donor mononuclear cells are infused into patients, is one of the few effective immunotherapeutic strategies that generate long-lasting tumor remissions. We previously demonstrated that chronic myelogenous leukemia (CML) patients treated with DLI develop high-titer plasma antibodies specific for CML-associated antigens, the majority of which have been reported to bind nucleic acids These observations led us to predict that circulating antibody-antigen complexes in DLI-responsive patients carry nucleic acids that can engage innate immune sensors. Consistent with this, we report here that post-DLI plasma from 5 CML patients that responded to DLI treatment induced massive upregulation of MIP-1α, IP-10, and IFN-α in normal blood mononuclear cells.

Fungal pathogen recognition by scavenger receptors in nematodes and mammals.

Macrophages are important cells in the host resistance to fungal infections, and fungal recognition by macrophages triggers phagocytosis, intracellular killing, induction of inflammatory cytokines and chemokines, and initiation of the adaptive immune response. All of the receptors that mediate binding and engulfment of fungal pathogens and the signaling pathways triggered by fungal pathogens that regulate anti-fungal immunity are not fully understood. Using an RNAi screen we recently demonstrated that the C.