ACKR3 in Skin Homeostasis, an Overlooked Player in the CXCR4/CXCL12 Axis.

CXCL12 and its receptor CXCR4 emerge as critical regulators within the intricate network of processes ensuring skin homeostasis. In this review, we discuss their spatial distribution and function in steady-state skin; delve into their role in acute wound healing, with emphasis on fibrotic and regenerative responses; and explore their relevance in skin responses to commensals and pathogens. Given the lack of knowledge surrounding ACKR3, the atypical receptor of CXCL12, we speculate whether and how it might be involved in the processes mentioned earlier.

CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.

Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.

Optimized protocol for 3D epithelial cultures supporting human papillomavirus replication.

Human papillomaviruses (HPVs) are commensal viruses with pathogenic potential. Their life cycle requires the proliferation and differentiation of keratinocytes (KCs) to form pluristratified epithelia. Based on the original organotypic epithelial raft cultures protocol, we provide an updated workflow to optimally generate pluristratified human epithelia supporting the complete HPV replicative life cycle, here called 3D full-thickness epithelial cultures (3Deps).

[The cutaneous virome: from virology to personalized medicine].

The virome of the skin, defined as all viruses detected in the skin, represents a significant part of the microbiota. A much more recent discovery than the bacterial flora, the existence of the cutaneous virome has been revealed by recent metagenomic studies. The normal human skin virome is dominated by bacteriophages, Papillomaviridae, whose genomic diversity has proved extraordinary, and Polyomaviridae.

Reprogramming of connexin landscape fosters fast gap junction intercellular communication in human papillomavirus-infected epithelia.

Human papillomaviruses (HPVs) are highly prevalent commensal viruses that require epithelial stratification to complete their replicative cycle. While HPV infections are most often asymptomatic, certain HPV types can cause lesions, that are usually benign. In rare cases, these infections may progress to non-replicative viral cycles associated with high HPV oncogene expression promoting cell transformation, and eventually cancer when not cleared by host responses.

Severe CD8+ T Lymphopenia in WHIM Syndrome Caused by Selective Sequestration in Primary Immune Organs.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined.

Clinical and Hematologic Effects of Endotoxin in Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome Model Mice.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function CXCR4 mutations that promote severe panleukopenia caused by bone marrow retention of mature leukocytes. Consequently, WHIM patients develop recurrent bacterial infections; however, sepsis is uncommon. To study this clinical dichotomy, we challenged WHIM model mice with LPS.

HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources.

Despite the high prevalence of both cervico-vaginal human papillomavirus (HPV) infection and bacterial vaginosis (BV) worldwide, their causal relationship remains unclear. While BV has been presumed to be a risk factor for HPV acquisition and related carcinogenesis for a long time, here, supported by both a large retrospective follow-up study (n = 6,085) and extensive in vivo data using the K14-HPV16 transgenic mouse model, we report a novel blueprint in which the opposite association also exists. Mechanistically, by interacting with several core members (NEMO, CK1 and β-TrCP) of both NF-κB and Wnt/β-catenin signaling pathways, we show that HPV E7 oncoprotein greatly inhibits host defense peptide expression.

The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy.

Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment.

Case Report: Altered NK Cell Compartment and Reduced CXCR4 Chemotactic Response of B Lymphocytes in an Immunodeficient Patient With HPV-Related Disease.

The study of inborn errors of immunity (IEI) provides unique opportunities to elucidate the microbiome and pathogenic mechanisms related to severe viral infection. Several immunological and genetic anomalies may contribute to the susceptibility to develop Human Papillomavirus (HPV) pathogenesis. They include different acquired immunodeficiencies, or mutations underlying epidermodysplasia verruciformis (EV) syndrome and multiple IEI.

Multi-Tissue Characterization of GILZ Expression in Dendritic Cell Subsets at Steady State and in Inflammatory Contexts.

Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ).

CXCR4 signaling controls dendritic cell location and activation at steady state and in inflammation.

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked.

The G Protein-Coupled Receptor Kinases (GRKs) in Chemokine Receptor-Mediated Immune Cell Migration: From Molecular Cues to Physiopathology.

Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes.

The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication.

The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43).

The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting.

Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression.

A chemotaxis model to explain WHIM neutrophil accumulation in the bone marrow of WHIM mouse model.

Neutrophils are essential immune cells that defend the host against pathogenic microbial agents. Neutrophils are produced in the bone marrow and are retained there through CXCR4-CXCL12 signaling. However, patients with the Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome are prone to infections due to increased accumulation of neutrophils in the bone marrow leading to low numbers of circulating neutrophils.

Identification by high-throughput sequencing of HPV variants and quasispecies that are untypeable by linear reverse blotting assay in cervical specimens.

The linear reverse blotting assays are valid methods for accurate human papillomavirus (HPV) typing required to manage women at risk of developing cervical cancer. However, some samples showed a positive signal in HPV lines but failed to display a positive signal in subsequent typing lines (designated as HPV-X), which indicate that certain types were not available on the respective typing blots. The aim of this study is to elucidate the types or variants of HPV through the high-throughput sequencing (HTS) of 54 ASCUS cervical samples in which the viruses remained untypeable with INNO LiPA HPV assays.

Atypical Chemokine Receptor 3 (ACKR3): A Comprehensive Overview of its Expression and Potential Roles in the Immune System.

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes, particularly during development. Its CXCL11 and CXCL12 scavenging activity and atypical signaling properties, together with a new array of other nonchemokine ligands, have established ACKR3 as a main regulator of physiologic processes at steady state and during inflammation. Here, we present a comprehensive review of ACKR3 expression in mammalian tissues in search of a possible connection with the receptor function.