A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.

Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon and skin are known, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the non-intestinal mucosal tissues and distinguishes them from intestinal mucosae.

CD200R neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells.

Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200R neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (T) cells.

Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes.

Aims: Chemoattractants and their cognate receptors are essential for leucocyte recruitment during atherogenesis, and atherosclerotic plaques preferentially occur at predilection sites of the arterial wall with disturbed flow (d-flow). In profiling the endothelial expression of atypical chemoattractant receptors (ACKRs), we found that Ackr5 (CCRL2) was up-regulated in an endothelial subpopulation by atherosclerotic stimulation. We therefore investigated the role of CCRL2 and its ligand chemerin in atherosclerosis and the underlying mechanism.

Development of a rapid image-based high-content imaging screening assay to evaluate therapeutic antibodies against the monkeypox virus.

Antibody-based therapy is emerging as a critical therapeutic countermeasure to treat acute viral infections by offering rapid protection against clinical disease. The advancements in structural biology made it feasible to rationalize monoclonal antibodies (mAbs) by identifying key and, possibly, neutralizing epitopes of viral proteins for therapeutic purposes. A critical component in assessing mAbs during pandemics requires the development of rapid but detailed methods to detect and quantitate the neutralization activity.

Soluble mediators in the function of the epidermal-immune-neuro unit in the skin.

Skin is the largest, environmentally exposed (barrier) organ, capable of integrating various signals into effective defensive responses. The functional significance of interactions among the epidermis and the immune and nervous systems in regulating and maintaining skin barrier function is only now becoming recognized in relation to skin pathophysiology. This review focuses on newly described pathways that involve soluble mediator-mediated crosstalk between these compartments.

Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling.

Lung-resident neutrophils need to be tightly regulated to avoid degranulation- and cytokine-associated damage to fragile alveolar structures that can lead to fatal outcomes. Here we show that lung neutrophils (LNs) express distinct surface proteins and genes that distinguish LNs from bone marrow and blood neutrophils. Functionally, LNs show impaired migratory activity toward chemoattractants and produce high levels of interleukin-6 (IL-6) at steady state and low levels of tumor necrosis factor-α in response to lipopolysaccharide (LPS) challenge.

Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice.

Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein.

Chemerin-Derived Peptide Val-Pro Is Effective in Limiting Methicillin-Resistant Skin Infection.

Chemerin-derived peptide Val-Pro (p4) restricts the growth of a variety of skin-associated bacteria, including methicillin-resistant (MRSA). To better understand the antimicrobial potential of chemerin peptide, we compared p4 activity against MRSA to cathelicidin LL-37, one of the key endogenous peptides implicated in controlling the growth of . The efficacy of p4 was also validated in relevant experimental models of skin pathology, such as topical skin infection with community-acquired MRSA, and in the context of skin inflammatory diseases commonly associated with colonization with , such as atopic dermatitis (AD).

CCR2 deficiency alters activation of microglia subsets in traumatic brain injury.

In traumatic brain injury (TBI), a diversity of brain resident and peripherally derived myeloid cells have the potential to worsen damage and/or to assist in healing. We define the heterogeneity of microglia and macrophage phenotypes during TBI in wild-type (WT) mice and Ccr2 mice, which lack macrophage influx following TBI and are resistant to brain damage. We use unbiased single-cell RNA sequencing methods to uncover 25 microglia, monocyte/macrophage, and dendritic cell subsets in acute TBI and normal brains.

Redox Active Antimicrobial Peptides in Controlling Growth of Microorganisms at Body Barriers.

Epithelia in the skin, gut and other environmentally exposed organs display a variety of mechanisms to control microbial communities and limit potential pathogenic microbial invasion. Naturally occurring antimicrobial proteins/peptides and their synthetic derivatives (here collectively referred to as AMPs) reinforce the antimicrobial barrier function of epithelial cells. Understanding how these AMPs are functionally regulated may be important for new therapeutic approaches to combat microbial infections.

Bacteria Modify Their Sensitivity to Chemerin-Derived Peptides by Hindering Peptide Association With the Cell Surface and Peptide Oxidation.

Chronic inflammatory skin diseases like psoriasis alter the local skin microbiome and lead to complications such as persistent infection with opportunistic/pathogenic bacteria. Disease-associated changes in microbiota may be due to downregulation of epidermal antimicrobial proteins/peptides, such as antimicrobial protein chemerin. Here, we show that chemerin and its bioactive derivatives have differential effects on the viability of different genera of cutaneous bacteria.

Novel CD11bGr-1Sca-1 myeloid cells drive mortality in bacterial infection.

Extreme pathophysiological stressors induce expansion of otherwise infrequent leukocyte populations. Here, we found a previously unidentified CD11bGr-1 myeloid cell population that expresses stem cell antigen-1 (Sca-1) induced upon experimental infection with . Although CD11bGr-1Sca-1 cells have impaired migratory capacity and superoxide anion-producing activity, they secrete increased levels of several cytokines and chemokines compared to Sca-1 counterparts.

Chemerin Suppresses Breast Cancer Growth by Recruiting Immune Effector Cells Into the Tumor Microenvironment.

Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells.

A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis.

We examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594.

Novel CMKLR1 Inhibitors for Application in Demyelinating Disease.

Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy.

Support of Tumor Endothelial Cells by Chemokine Receptors.

Tumor-associated vascular endothelium comprises a specialized and diverse group of endothelial cells that, although not cancer themselves, are integral to cancer progression. Targeting the tumor vasculature can have significant efficacy in reducing tumor burden, although loss of efficacy due to acquisition of resistance mechanisms is common. Here we review mechanisms by which tumor endothelial cells (TEC) utilize chemokine receptors to support tumor progression.

DGAT1 inhibits retinol-dependent regulatory T cell formation and mediates autoimmune encephalomyelitis.

The balance of effector versus regulatory T cells (Tregs) controls inflammation in numerous settings, including multiple sclerosis (MS). Here we show that memory phenotype CD4 T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis (EAE), a widely studied animal model of MS, expressed high levels of mRNA for encoding diacylglycerol-O-acyltransferase-1 (DGAT1), an enzyme that catalyzes triglyceride synthesis and retinyl ester formation. DGAT1 inhibition or deficiency attenuated EAE, with associated enhanced Treg frequency; and encephalitogenic, DGAT1 in vitro-polarized Th17 cells were poor inducers of EAE in adoptive recipients.

Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention.

Chemerin [ [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine.

The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions.

Chemerin is a leukocyte attractant, adipokine, and antimicrobial protein abundantly produced in the skin epidermis. Despite the fact that most of the bactericidal activity present in human skin exudates is chemerin-dependent, just how chemerin shapes skin defenses remains obscure. Here we demonstrate that p4, a potent antimicrobial human chemerin peptide derivative, displays killing activity against pathogenic methicillin-resistant strains and suppresses microbial growth in a topical skin infection model.

The impact of chemerin or chemokine-like receptor 1 loss on the mouse gut microbiome.

Chemerin is an adipocyte derived signalling molecule (adipokine) that serves as a ligand activator of Chemokine-like receptor 1(CMKLR1). Chemerin/CMKLR1 signalling is well established to regulate fundamental processes in metabolism and inflammation. The composition and function of gut microbiota has also been shown to impact the development of metabolic and inflammatory diseases such as obesity, diabetes and inflammatory bowel disease.

A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models.

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels.

A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15.

Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived sushi containing domain-2 binding factor (CSBF), encoded by in the human and in the mouse, functions as a chemokine ligand for GPR15 (GPR15L).

Antimicrobial and Attractant Roles for Chemerin in the Oral Cavity during Inflammatory Gum Disease.

Periodontal inflammation is one of the most common chronic inflammatory conditions in humans. Despite recent advances in identifying and characterizing oral microbiota dysbiosis in the pathogenesis of gum disease, just how host factors maintain a healthy homeostatic oral microbial community or prevent the development of a pathogenic oral microbiota remains poorly understood. An important determinant of microbiota fate is local antimicrobial proteins.