Several studies have reported a strong association between plasma proteins and chronic obstructive pulmonary disease (COPD). However, the directionality and causality of the association and whether proteins effected COPD remain unclear. Therefore, we used Proteome-wide Mendelian randomization (MR) study and co-localization analyses to estimate the casual relationship between them. Summary-level data of 2923 plasma protein levels were extracted from a large-scale protein quantitative trait loci study including 54,219 individuals by the UK Biobank Pharma Proteomics Project. The outcome data for COPD and its subtypes were sourced from the FinnGen study. MR analysis was conducted to estimate the associations between protein and COPD and its subtypes risk. Additionally, phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. STROBE MR guidelines are followed for the study. We assessed the effect of 1929 plasma proteins on COPD. We found that Seven proteins, 4 proteins, and 3 proteins were associated with overall COPD, early-onset COPD, and later-onset COPD risk, respectively. MHC class I polypeptide-related sequence B_A (MICB_MICA) and tyrosine-protein kinase receptor tie-1 (TIE-1) would increase 8% and 27% COPD risk (MICB_MICA: odds ratios [OR], 1.08; 95% CI, 1.05-1.10; PFDR = 2.53 × 10-5; TIE-1: OR, 1.27; 95% CI, 1.13-1.43; PFDR = .012). There was negative association of Septin-8 and Butyrophilin subfamily 1 member A1 (BTN1A1) with overall COPD risk (Septin-8: OR, 0.68; 95% CI, 0.57-0.79; PFDR = 8.00 × 10-4 BTN1A1: OR, 0.82; 95% CI, 0.75-0.90; PFDR = .010). There was a protective effect of BTN1A1 on early COPD incidence (OR, 0.72; 95% CI, 0.63-0.83; PFDR = .002). However, there was no evidence indicating a shared causal variant between the other proteins and COPD and its subtypes in these regions (all posterior probability.H4 < .8). The study revealed the causal relationship between several plasma proteins and COPD and its subtypes, providing new theoretical support for understanding COPD.

Fibroblast Growth Factor 21 (FGF21), a pivotal member of the fibroblast growth factor family, exhibits multifaceted biological functions, including the modulation of pro-inflammatory cytokines and metabolic regulation. Recent research has revealed that in impaired skin tissues, FGF21 and its receptors are upregulated and play a significant role in accelerating the wound healing process. However, the clinical application of FGF21 is severely limited by its short in vivo half-life: this factor is often degraded by enzymes before it can exert its therapeutic effects. To address this limitation, the transdermal drug delivery system (TDDS) has emerged as an innovative approach that enables sustained drug release, significantly prolonging the therapeutic duration. Leveraging genetic recombination technology, research teams have ingeniously fused FGF21 with cell-penetrating peptides (CPPs) to construct recombinant FGF21 complexes. These novel conjugates can efficiently penetrate the epidermal barrier and achieve sustained and stable pharmacological activity through TDDS. This review systematically analyzes the potential signaling pathways by which FGF21 accelerates skin wound repair, summarizes the latest advancements in TDDS technology, explores the therapeutic potential of FGF21, and evaluates the efficacy of CPP fusion tags. The manuscript not only proposes an innovative paradigm for the application of FGF21 in skin injury treatment but also provides new insights into its use in transdermal delivery, marking a significant step toward overcoming existing clinical therapeutic challenges. From a clinical medical perspective, this innovative delivery system holds promise for addressing the bioavailability issues of traditional FGF21 therapies, offering new strategies for the clinical treatment of metabolism-related diseases and wound healing. With further research, this technology holds vast potential for clinical applications in hard-to-heal wounds such as diabetic foot ulcers and burns.

Langerhans cell histiocytosis (LCH) rarely presents in the oral and maxillofacial region, and while isolated and small collections of Langerhans-type cells have been found in periapical cysts, there have been no reported cases of LCH arising in periapical cysts.

A 58-year-old female presented with isolated erythematous dry skin lesions and a radiolucent lesion of the anterior maxilla. Microscopic examination of the enucleation specimen revealed a periapical cyst with large collections of atypical cells with grooved folded nuclei with eosinophils consistent with LCH. Immunohistochemistry (IHC) was performed to confirm the diagnosis. BRAF mutation status was evaluated with the BRAF p. V600E antibody and the automated real-time PCR-based Idylla™ assay, capable of qualitative detection of 5 mutations in codon 600 of the BRAF gene.

The LCH cells were positive for S100, CD1a, and Langerin (CD 207) and negative for BRAF p. V600E mutations. Ki-67 was 45%.

The association of LCH with a periapical cyst could be explained by the active surveillance and migration of neoplastic Langerhans-type cells in blood to the site of apical chronic inflammation, in a patient with LCH. Careful attention to morphologic features in conjunction with Langerin IHC, helps exclude other closely-related dendritic tumours. BRAF p. V600E testing, ideally with real-time PCR assays, can help identify patients who may benefit from BRAF inhibitor therapies. New generations of sequencing that cover a large panel of genetic alterations beyond the frequent BRAF p. V600E mutations (e.g. rare in-frame BRAF deletions), could provide valuable information about the extent, prognosis and treatment of LCH patients.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. AD is a highly complex disease with different subtypes. Many elements of AD pathophysiology have been described, but if/how they interact with each other or which mechanisms are important in which patients is still unclear. Langerhans cells (LCs) are antigen-presenting cells (APCs) in the epidermis. Depending on the context, they can act either pro- or anti-inflammatory. Many different studies have investigated LCs in the context of AD and found them to be connected to all major mechanisms of AD pathophysiology. As APCs, LCs recruit other immune cells and shape the immune response, especially adaptive immunity via polarization of T cells. As sentinel cells, LCs are primary sensors of the skin microbiome and are important for the decision of immunity versus tolerance. LCs are also involved with the integrity of the skin barrier by influencing tight junctions. Finally, LCs are important cells in the neuro-immune crosstalk in the skin. In this review, we provide an overview about the many different roles of LCs in AD. Understanding LCs might bring us closer to a more complete understanding of this highly complex disease. Potentially, modulating LCs might offer new options for targeted therapies for AD patients.

Breast cancer is the second most commonly diagnosed cancer in women and the fifth leading cause of cancer-related deaths worldwide. It is a highly heterogeneous disease, consisting of multiple subtypes that vary significantly in clinical characteristics and survival outcomes. Triple-negative breast cancer (TNBC) is a particularly aggressive and challenging subtype of breast cancer. Several immunotherapeutic approaches have been tested in patients with TNBC to improve disease outcomes, including the administration of dendritic cell (DC)-based vaccines. DCs are a heterogeneous cell population that play a crucial role in bridging the innate and adaptive immune systems. Therefore, DCs have been increasingly used in cancer vaccines due to their ability to prime and boost antigen specific T-cell immune responses. This review aims to provide a comprehensive overview of TNBC, including potential targets and pharmacological strategies, as well as an overview of DCs and their relevance in TNBC. In addition, we review ongoing clinical trials and shed light on the evolving landscape of DC-based immunotherapy for TNBC.

Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) in linking innate and adaptive immune responses. In addition to presenting antigens to T cells, DCs must also provide co-stimulatory signals along with cytokines for T cells to induce an appropriate cellular immune response. Tolerance is also established and maintained by DCs under homeostatic circumstances. There is remarkable phenotypic heterogeneity in DCs, each with different functional flexibility and specific expression of various markers. The three primary categories of DCs comprise conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). Langerhans cells (LCs) are another type of DCs, which are found in the skin's epidermal layer. DCs may be positioned or triggered inappropriately as a result of dysregulation of DC. This phenomenon can cause an imbalance in immune responses and even immune-related pathological disorders, i.e., autoimmune diseases and malignancies. Herein, by reviewing the ontogeny, biology, characteristics, and function of DCs subsets in immune system, we discuss the contribution of these cells in the mentioned immune-related disorders.

The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.

Caffeine has recently attracted attention as a potential remedy for hair loss. In the present review, we look into the molecule's possible mechanisms of action and pharmacodynamics. At the molecular level, it appears that the physiological effects of caffeine are mainly due to the molecule's interaction with adenosine pathways which leads to an increase in cAMP level and the stimulation of metabolic activity in the hair follicle. Moreover, caffeine also acts as an antioxidant and may prevent degenerative processes. While the intact stratum corneum seems virtually impenetrable to caffeine and a range of physical and chemical methods have been proposed to facilitate its penetration, hair follicles seem to be both a main entry route into the skin and target structures for caffeine at the same time. Caffeine readily forms bonds with water and other molecules which may influence its bioavailability and should be taken into account when engineering future hair products. The results of clinical studies published so far seem promising; however, the majority of the studies of caffeine-based hair loss products offer a very low level of evidence due to considerable flaws in study designs. Nevertheless, the metabolic activity of caffeine and its ability to enter and accumulate in the hair follicles combined with the results of available clinical trials seem to indicate that caffeine could indeed prove as an effective and safe option in the management of hair loss.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs, and various nonlymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single-cell suspensions from human nonlymphoid tissues including lung, skin, gingiva, intestine as well as from tumors and tumor-draining lymph nodes with a subsequent analysis of dendritic cells by flow cytometry. Further, prepared single-cell suspensions can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, etc. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

The skin serves as the first protective barrier for nonspecific immunity and encompasses a vast network of skin-associated immune cells. Atopic dermatitis (AD) is a prevalent inflammatory skin disease that affects individuals of all ages and races, with a complex pathogenesis intricately linked to genetic, environmental factors, skin barrier dysfunction as well as immune dysfunction. Individuals diagnosed with AD frequently exhibit genetic predispositions, characterized by mutations that impact the structural integrity of the skin barrier. This barrier dysfunction leads to the release of alarmins, activating the type 2 immune pathway and recruiting various immune cells to the skin, where they coordinate cutaneous immune responses. In this review, we summarize experimental models of AD and provide an overview of its pathogenesis and the therapeutic interventions. We focus on elucidating the intricate interplay between the immune system of the skin and the complex regulatory mechanisms, as well as commonly used treatments for AD, aiming to systematically understand the cellular and molecular crosstalk in AD-affected skin. Our overarching objective is to provide novel insights and inform potential clinical interventions to reduce the incidence and impact of AD.

Oral squamous cell carcinoma (OSCC) arises in the oral epithelium, a tissue in which immune surveillance is mediated by its primary resident leukocytes, Langerhans cells (LCs), and γδT cells. Under steady-state conditions, LCs and γδT cells play a critical role in maintaining oral mucosal homeostasis. As antigen-presenting cells of stratified epithelia, LCs respond to various challenges faced by the epithelium, orchestrating innate, and adaptive immune responses in order to resolve them. γδT cells also sense diverse epithelial insults and react rapidly through cytokine production and cytolytic activity. These epithelial sentinels are also considered to be the first leukocytes in the oral epithelium to encounter early carcinogenic events that have the potential of becoming OSCC. As evident in many malignancies, leukocyte populations help prevent cancer development although they also promote tumor progression. OSCC is no exception, as studies have reported both anti- and pro-tumor roles of LCs and γδT cells. In this review, we summarize the ontogeny of LCs and γδT cells in the oral epithelium and discuss their role in OSCC.

Langerhans cells (LCs) are the key antigen-presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti-inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single-cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs' function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases.

Feline histiocytic diseases are uncommon and rarely reported. Feline progressive histiocytosis (FPH) is the most common histiocytic disease in cats, predominantly affecting middle-aged animals. The most common presentation is the cutaneous form with solitary or multiple cutaneous nodules. A female, mixed-breed 6-year-old cat was presented with a 9-month history of a nodule in the nasal planum and was diagnosed by histopathology with histiocytic proliferation. At the time of diagnosis, new nodules were discovered on the lower lip, digit, and two lesions in the tail region, with the largest measuring 1.5 cm. Supplementary immunohistochemistry, showed immunolabeling for Iba-1 that in combination with the clinical course of the disease, confirmed the diagnosis of FPH. No response to chemotherapy treatment with lomustine alternated with doxorubicin was achieved. Toceranib phosphate resulted in a transient response and, stable disease for a short period (6 weeks). Electrochemotherapy with bleomycin was initiated and resulted in partial remission. Later on, chlorambucil was also started. Ultimately, the combination of all three treatments led to a complete response and disappearance of all the lesions. FPH is considered a disease resistant to various treatments, and effective treatments have not been reported. In this case report, we describe a successful multimodal therapeutic approach that resulted in complete resolution of the FPH and long-term survival (460 days without external lesions at the time of death). Further studies are necessary to confirm the efficacy of this therapeutic approach.

Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.

Skin provides a physical and immune barrier to protect the body from foreign substances, microbial invasion, and desiccation. Aging reduces the barrier function of skin and its rate of repair. Aged skin exhibits decreased mitochondrial function and prolonged low-level inflammation that can be seen in other organs with aging. Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), an important transcriptional coactivator, plays a central role in modulating mitochondrial function and antioxidant production. Mitochondrial function and inflammation have been linked to epidermal function, but the mechanisms are unclear. The aim of this review is to discuss the mechanisms by which PGC-1α might exert a positive effect on aged skin barrier function. Initially, we provide an overview of the function of skin under physiological and aging conditions, focusing on the epidermis. We then discuss mitochondrial function, oxidative stress, cellular senescence, and inflamm-aging, the chronic low-level inflammation observed in aging individuals. Finally, we discuss the effects of PGC-1α on mitochondrial function, as well as the regulation and role of PGC-1α in the aging epidermis.

In the twenty- first century, there is widespread agreement that in addition to lung cancer, emphysema, and chronic bronchitis, cigarette smoking causes accumulation of pigmented macrophages, interstitial fibrosis, and Langerhans cell proliferation in various permutations. These histologic changes remain subclinical in some patients and produce clinical manifestations and imaging abnormalities in others. Debate surrounds terminology of these lesions, which are often grouped together under the umbrella of "smoking-related interstitial lung disease." This review summarizes modern concepts in our understanding of these abnormalities and explains how the recognition of smoking-related interstitial fibrosis has advanced the field.

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.

Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated.

To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues.

In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated.

Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.

Resident tissue macrophages (RTMs) encompass a highly diverse set of cells abundantly present in every tissue and organ. RTMs are recognized as central players in innate immune responses, and more recently their importance beyond host defense has started to be highlighted. Despite sharing a universal name and several canonical markers, RTMs perform remarkably specialized activities tailored to sustain critical homeostatic functions of the organs they reside in. These cells can mediate neuronal communication, participate in metabolic pathways, and secrete growth factors. In this Review, we summarize how the division of labor among different RTM subsets helps support tissue homeostasis. We discuss how the local microenvironment influences the development of RTMs, the molecular processes they support, and how dysregulation of RTMs can lead to disease. Last, we highlight both the similarities and tissue-specific distinctions of key RTM subsets, aiming to coalesce recent classifications and perspectives into a unified view.

Dendritic cells (DCs) are specialized antigen-presenting cells that are crucial for maintaining self-tolerance, initiating immune responses against pathogens, and patrolling body compartments. Despite promising aspects, DC-based immunotherapy faces challenges that include limited availability, immune escape in tumors, immunosuppression in the tumor microenvironment, and the need for effective combination therapies. A further limitation in DC-based immunotherapy is the low population of migratory DC (around 5%-10%) that migrate to lymph nodes (LNs) through afferent lymphatics depending on the LN draining site. By increasing the population of migratory DCs, DC-based immunotherapy could enhance immunotherapeutic effects on target diseases. This paper reviews the importance of DC migration and current research progress in the context of DC-based immunotherapy.

Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R.

Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL.

The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls.

We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities.

The inflammatory response during cutaneous leishmaniasis (CL) involves immune and non-immune cell cooperation to contain and eliminate Leishmania parasites. The orchestration of these responses is coordinated primarily by CD4+ T cells; however, the disease outcome depends on the Th cell predominant phenotype. Although Th1 and Th2 phenotypes are the most addressed as steers for the resolution or perpetuation of the disease, Th17 cell activities, especially IL-17 release, are recognized to be vital during CL development. Th17 cells perform vital functions during both acute and chronic phases of CL. Overall, Th17 cells induce the migration of phagocytes (neutrophils, macrophages) to the infection site and CD8+ T cells and NK cell activation. They also provoke granzyme and perforin secretion from CD8+ T cells, macrophage differentiation towards an M2 phenotype, and expansion of B and Treg cells. Likewise, immune cells from the inflammatory infiltrate have modulatory activities over Th17 cells involving their differentiation from naive CD4+ T cells and further expansion by generating a microenvironment rich in optimal cytokines such as IL-1β, TGF-β, IL-6, and IL-21. Th17 cell activities and synergies are crucial for the resistance of the infection during the early and acute stages; however, if unchecked, Th17 cells might lead to a chronic stage. This review discusses the synergies between Th17 cells and the inflammatory infiltrate and how these interactions might destine the course of CL.

The emergence of severe sepsis is contingent upon the occurrence of a cytokine storm (CS), a multifaceted process intricately entwined with the temporal dimension, thereby rendering the infection response remarkably intricate. Consequently, it becomes imperative to discern and accurately identify the optimal timing for interventions, predicated upon the dynamic timeline of inflammatory changes. Moreover, the administration of exogenous low-dose pro-inflammatory agents has exhibited the potential to impede the relentless progression of the inflammatory cascade. Hence, the present study aims to scrutinize the impact of exogenous Local Inflammatory Response (eLIR) on the body surface in the context of the inflammatory cascade during sepsis, within a temporal framework, with a particular emphasis on the point of exacerbation of inflammation.

Rats were induced sterile sepsis by intraperitoneal injection of zymosan (ZY) at an appropriate dosage. The temporal progression of inflammatory changes and eLIR effects were described based on the trend of serum crucial inflammatory cytokines, tring to quest time-point of inflammatory aggravation in sepsis. Then, the varying degrees of surface inflammation caused by eLIR on this time point leading to the final effects on the inflammatory cascade response were explored. In addition, given the authentic pathological progression of sepsis, further observation was conducted on the impact of another intervention timing of eLIR on the inflammatory cascade. The survival rate was measured. Serum and organ related inflammatory cytokines were detected, and organ histopathology was investigated.

In present study, a dosage of 600 mg/kg ZY was found to be optimal for the sterile sepsis model. Initiating eLIR 6 h prior to ZY injection, the maximum effect point of eLIR could be precisely align with the inflammatory aggravation point of sterile sepsis. Initiating eLIR at this time, 3 sessions of eLIR were found to be more effective than 1 or 2 sessions in mitigating inflammatory responses during the initial stage of inflammation and the peak of inflammation. Notably, the findings also suggested that this intervention improve survival rate. In addition, the anti-inflammatory efficacy has been substantially diminished by the prompt initiation of 3 sessions of eLIR immediately after ZY injection at the onset of sepsis. Similarly, the current findings did not demonstrate a statistically significant enhancement in survival rates with eLIR at this time point.

Compared with the initial stage of inflammation, low-scale inflammation caused by a certain intensity of eLIR (3 sessions) on the body surface can more effectively pry the inflammation aggravation time-point, thereby shifting the pro-inflammatory to anti-inflammatory milieu, impeding the disproportionate cytokines release in inflammatory diseases, slowing down the inflammatory cascade, and improving the survival rate of sepsis.

Feline pulmonary Langerhans cells histiocytosis (PLCH) is a rare disorder that results in progressive respiratory failure secondary to pulmonary parenchymal infiltration with Langerhans cells (LCs). A diagnosis of PLCH is proposed based on the clinical features and pathological findings and confirmed based on the infiltrating histiocytic cells. There are few documented cases of feline PLCH, and this case report of PLCH in an African Lion could present new information and aspects of this feline histiocytic disease.

An African lion at Hohhot Zoo showing severe hyporexia and dyspnea with subsequent mental depression and emaciation died of exhaustion after a 35-day course of illness. Empirical treatment did not have a significant effect. An autopsy revealed that the lungs were enlarged and hardened due to infiltrative lesions, with many yellowish-white foci in all the lobes and sections. Furthermore, the kidneys were atrophied and had scattered grayish-white lesions on the surface. At the same time, congestion was widely distributed in various locations, including the liver, subcutaneous loose connective tissues, serosal surface and other tissues and organs. Histologically, proliferative histiocytic cells (PHCs) were scattered in the alveolar cavities, bronchioles and submucosa of bronchioles, with evident cellular and nuclear pleomorphism, and thus the alveolar septa were obliterated. The histopathological changes in other organs included chronic sclerosing glomerulonephritis, proliferated Kupffer cells in the liver, adrenal edema and interstitial connective tissue hyperplasia, as well as atrophy of the small intestines and spleen. Furthermore, immunohistochemical analysis results were strongly positive for CD1a, vimentin, S100 and E-cadherin in the membrane or cytoplasm of PHCs, supporting an LC phenotype.

Here, we present a rare pulmonary Langerhans cell histiocytosis case in an African lion.

Contemporary research in the field of microbiota shows that commensal bacteria influence physiological activity of different organs and systems of a human organism, such as brain, lungs, immune and metabolic systems. This influence is realized by various processes. One of them is trough modulation of immune mechanisms. Interactions between microbiota and the human immune system are known to be complex and ambiguous. Dendritic cells (DCs) are unique cells, which initiate the development and polarization of adaptive immune response. These cells also interconnect native and specific immune reactivity. A large set of biochemical signals from microbiota in the form of different microbiota associated molecular patterns (MAMPs) and bacterial metabolites that act locally and distantly in the human organism. As a result, commensal bacteria influence the maturity and activity of dendritic cells and affect the overall immune reactivity of the human organism. It then determines the response to pathogenic microorganisms, inflammation, associated with different pathological conditions and even affects the effectiveness of vaccination.

For over a decade, the skin sensitization Adverse Outcome Pathway (AOP) has served as a useful framework for development of novel in chemico and in vitro assays for use in skin sensitization hazard and risk assessment. Since its establishment, the AOP framework further fueled the existing efforts in new assay development and stimulated a plethora of activities with particular focus on validation, reproducibility and interpretation of individual assays and combination of assay outputs for use in hazard/risk assessment. In parallel, research efforts have also accelerated in pace, providing new molecular and dynamic insight into key events leading to sensitization. In light of novel hypotheses emerging from over a decade of focused research effort, mechanistic evidence relating to the key events in the skin sensitization AOP may complement the tools currently used in risk assessment. We reviewed the recent advances unraveling the complexity of molecular events in sensitization and signpost the most promising avenues for further exploration and development of useful assays.

Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets1-3. A myriad of studies have highlighted their central role in immune function4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1β induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.

Since the skin limits the distribution of intradermal vaccines, a large number of dendritic cells in the skin cannot be fully utilized to elicit a more effective immune response. Here, we loaded the antigen to the surface of the flagellate bacteria that was modified by cationic polymer, thus creating antigen-loaded flagellate bacteria (denoted as 'FB-Ag') to overcome the skin barrier and perform the active delivery of antigen in the skin. The FB-Ag showed fast speed (∼0.2 μm s-1) and strong dendritic cell activation capabilities in the skin model in vitro. In vivo, the FB-Ag promoted the spread of antigen in the skin through active movement, increased the contact between Intradermal dendritic cells and antigen, and effectively activated the internal dendritic cells in the skin. In a mouse of pulmonary metastatic melanoma and in mice bearing subcutaneous melanoma tumor, the FB-Ag effectively increased antigen-specific therapeutic efficacy and produced long-lasting immune memory. More importantly, the FB-Ag also enhanced the level of COVID-19 specific antibodies in the serum and the number of memory B cells in the spleen of mice. The movement of antigen-loaded flagellate bacteria to overcome intradermal constraints may enhance the activation of intradermal dendritic cells, providing new ideas for developing intradermal vaccines.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.