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Th17 cell plasticity is associated with pathogenicity in chronic inflammation. In a model of periodontitis, McClure et al. (https://doi.org/10.1084/jem.20232015) describe location-dependent divergence in Th17 plasticity, with surprisingly limited conversion in inflamed gingiva but emergence of protective exTh17-TfH cells in draining LN that enhance protective antibody., (© 2024 McGeachy.)

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis., (© 2024 McClure et al.)

For decades, the Th1/2 paradigm has been used to classify immune responses as either Th1 or Th2-biased. However, in recent years, a staggering amount of evidence has emerged to support rejection of the classical Th1/Th2 paradigm, such as the discoveries of new helper T cell subsets, helper T cell plasticity and protective mixed-Th1/Th2 responses. This opinion piece investigates the shortcomings of classical Th1/Th2 paradigm in the context of recent works, with the goal of facilitating the development of newer models to represent the diversity of Th cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This issue highlights and details the program and scientific presentations at the International Eosinophil Society's 12th biennial symposium, which was held in Hamilton, Ontario, Canada, in July 2023. The meeting included sessions on regulation of eosinophil development; cell death, stress, and autophagy in eosinophils; local immunity interactions of eosinophils with multiple cell types; eosinophils in host defense; eosinophils and mast cells in gastrointestinal disorders; reciprocal interactions between eosinophils and the microbiome in homeostasis and dysbiosis; and eosinophils in tissue injury and repair and in tumor biology and cancer therapy. There was a mixture of special invited lectures and cutting-edge abstracts on specific aspects of eosinophil science, as well as enlivened pro-con debates on targeting eosinophils with biologics. A major thrust and overarching theme was that eosinophils exhibit remarkable plasticity and heterogeneity in executing their functions both in homeostasis and in pathobiology; there is a new "eo-verse" to understand. We trust that this special volume of the Journal of Leukocyte Biology will be of interest across many disciplines and medical subspecialties in biomedical sciences and demonstrate both the complexity and versatility of the eosinophil in biology and medicine., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

The mechanisms that negatively regulate inflammation upon a pathogenic stimulus are crucial for the maintenance of tissue integrity and organ function. T regulatory cells are one of the main drivers in controlling inflammation. The ability of T regulatory cells to adapt to different inflammatory cues and suppress inflammation is one of the relevant features of T regulatory cells. During this process, T regulatory cells express different transcription factors associated with their counterparts, Th helper cells, including Tbx21, GATA-3, Bcl6, and Rorc. The acquisition of this transcription factor helps the T regulatory cells to suppress and migrate to the different inflamed tissues. Additionally, the T regulatory cells have different mechanisms that preserve stability while acquiring a particular T regulatory cell subtype. This review focuses on describing T regulatory cell subtypes and the mechanisms that maintain their identity in health and diseases., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Pro-inflammatory CD4 + T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (T H 17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in T H 17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (T H 1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover T H 17 to T H 1 cell plasticity in the human kidney in the context of renal autoimmunity.

Phagocytic microglia such as proliferative region-associated microglia and disease-associated microglia appear in the brain transiently during development and across various brain pathologies, but their function and degree of plasticity remain unclear. In this issue of Immunity, Barclay et al. established a novel Clec7a-CreER T2 mouse line to uncover the plasticity of this cell state and its role in a model of myelin injury., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The synovial fluid (SF) microenvironment in rheumatoid arthritis (RA) may alter the stability and function of Tregs. In the present study, we assessed cytokine levels and percentage of Tregs, Tregs expressing CXCR3 (Th1-like Treg), CCR6 (Th17-like Treg) in RA peripheral blood (PB) and RA-SF using fluorescence cytometry. Effect of autologous SF on plasticity and function of RA-PB Tregs (pTregs; CD4 + CD25 hi CD127 Lo/- ) and induced vimentin-pulsed Tregs (iTregs VIM ) was assessed in vitro. Cytokines and percentage of Th1-like and Th17-like Tregs were higher in RA-PB than OA-PB; higher in RA-SF than osteoarthritis (OA)-SF. Compared to OA-SF exposed OA-pTregs, RA-SF exposed RA-pTregs showed higher percentage of Th1-like (11% vs 20%) and Th17-like (16% vs 36%) Tregs; higher T-bet (p = 0.0001), RORγ (p = 0.0001) and lower FOXP3 (p = 0.0001) gene expression; and diminished percentage suppression of autologous T effector cells (36% vs 74%). RA-SF exposed iTregs VIM showed increased percentage of Th1-like and Th17-like Tregs compared to iTregs VIM exposed to AB serum (8% vs 0.1%; 21% vs 0.1%). IL-2, Tocilizumab and 5-azacytidine reduced the conversion of iTregs VIM (8% vs 2.4%; 21% vs 6.9%), when used in combination. To conclude, microenvironment in the RA synovial fluid is possibly responsible for conversion of pTregs into Th-like Tregs and their functional loss. A blockade of cytokine receptors and methyl transferases could inhibit Tregs conversion, providing clinical relevance for future Tregs targeting therapies., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interests., (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Regulatory T cells (Tregs) are essential for maintaining the immune balance in normal and pathological conditions. In autoimmune diseases and transplantation, they restrain the loss of self-tolerance and promote engraftment, whereas in cancer, an increase in Treg numbers is mostly associated with tumor growth and poor prognosis. Numerous markers and their combinations have been used to identify Treg subsets, demonstrating the phenotypic diversity of Tregs. The complexity of Treg identification can be hampered by the unstable expression of some markers, the decrease in the expression of a specific marker over time or the emergence of a new marker. It remains unclear whether such phenotypic shifts are due to new conditions or whether the observed changes are due to initially different populations. In the first case, cellular plasticity is observed, whereas in the second, cellular heterogeneity is observed. The difference between these terms in relation to Tregs is rather blurred. Considering the promising perspectives of Tregs in regenerative cell-based therapy, the existing confusing data on Treg phenotypes require further investigation and analysis. In our review, we introduce criteria that allow us to distinguish between the heterogeneity and plasticity of Tregs normally and pathologically, taking a closer look at their diversity and drawing the line between two terms.

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissue-resident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Wang and Li.)

Head and neck squamous cell carcinoma (HNSCC) rank among the most prevalent types of head and neck cancer globally. Unfortunately, a significant number of patients receive their diagnoses at advanced stages, limiting the effectiveness of available treatments. The tumor microenvironment (TME) is a pivotal player in HNSCC development, with macrophages holding a central role. Macrophages demonstrate diverse functions within the TME, both inhibiting and facilitating cancer progression. M1 macrophages are characterized by their phagocytic and immune activities, while M2 macrophages tend to promote inflammation and immunosuppression. Striking a balance between these different polarization states is essential for maintaining overall health, yet in the context of tumors, M2 macrophages typically prevail. Recent efforts have been directed at controlling the polarization states of macrophages, paving the way for novel approaches to cancer treatment. Various drugs and immunotherapies, including innovative treatments based on macrophages like engineering macrophages and CAR-M cell therapy, have been developed. This article provides an overview of the roles played by macrophages in HNSCC, explores potential therapeutic targets and strategies, and presents fresh perspectives on the future of HNSCC treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Chu, Zheng, Gu, Hu, He and Shen.)

Ribosomal proteins are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein. However, in this study, we show that Rpl22-like1 (Rpl22l1) regulates hematopoiesis without affecting ribosome biogenesis or bulk protein synthesis. Conditional loss of murine Rpl22l1 using stage or lineage-restricted Cre drivers impairs development of several hematopoietic lineages. Specifically, Tie2-Cre-mediated ablation of Rpl22l1 in hemogenic endothelium impairs the emergence of embryonic hematopoietic stem cells. Ablation of Rpl22l1 in late fetal liver progenitors impairs the development of B lineage progenitors at the pre-B stage and development of T cells at the CD44 - CD25 + double-negative stage. In vivo labeling with O -propargyl-puromycin revealed that protein synthesis at the stages of arrest was not altered, indicating that the ribosome biogenesis and function were not generally compromised. The developmental arrest was associated with p53 activation, suggesting that the arrest may be p53-dependent. Indeed, development of both B and T lymphocytes was rescued by p53 deficiency. p53 induction was not accompanied by DNA damage as indicated by phospho-γH2AX induction or endoplasmic reticulum stress, as measured by phosphorylation of EIF2α, thereby excluding the known likely p53 inducers as causal. Finally, the developmental arrest of T cells was not rescued by elimination of the Rpl22l1 paralog, Rpl22, as we had previously found for the emergence of hematopoietic stem cells. This indicates that Rpl22 and Rpl22l1 play distinct and essential roles in supporting B and T cell development., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs. Moreover, administration of a high-fat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes., Competing Interests: Disclosures: R.A. DePinho reported being a Founder and Advisor for Tvardi Therapeutics, Asylia Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, and Sporos Bioventures. The focus of these companies is not directly related to the content of this manuscript. S. Gordon reported personal fees from Verseau, Myeloid Therapeutics, and Alnylam outside the submitted work. No other disclosures were reported., (© 2021 Masetti et al.)

Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2022 Krzywinska et al.)

Human NK cells are comprised of phenotypic subsets, whose potentially unique functions remain largely unexplored. C-X-C-motif-chemokine-receptor-6 (CXCR6) + NK cells have been identified as phenotypically immature tissue-resident NK cells in mice and humans. A small fraction of peripheral blood (PB)-NK cells also expresses CXCR6. However, prior reports about their phenotypic and functional plasticity are conflicting. In this study, we isolated, expanded, and phenotypically and functionally evaluated CXCR6 + and CXCR6 - PB-NK cells, and contrasted results to bulk liver and spleen NK cells. We found that CXCR6 + and CXCR6 - PB-NK cells preserved their distinct phenotypic profiles throughout 14 days of in vitro expansion ("day 14"), after which phenotypically immature CXCR6 + PB-NK cells became functionally equivalent to CXCR6 - PB-NK cells. Despite a consistent reduction in CD16 expression and enhanced expression of the transcription factor Eomesodermin (Eomes), day 14 CXCR6 + PB-NK cells had superior antibody-dependent cellular cytotoxicity (ADCC) compared to CXCR6 - PB-NK cells. Further, bulk liver NK cells responded to IL-15, but not IL-2 stimulation, with STAT-5 phosphorylation. In contrast, bulk splenic and PB-NK cells robustly responded to both cytokines. Our findings may allow for the selection of superior NK cell subsets for infusion products increasingly used to treat human diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Angelo, Hogg, Abeynaike, Bimler, Vargas-Hernandez and Paust.)

Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.

Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mohamud Yusuf, Hagemann, Ludewig, Gunzer and Hermann.)

Background: Immunohistochemical analysis of granule-associated proteases has revealed that human lung mast cells constitute a heterogeneous population of cells, with distinct subpopulations identified. However, a systematic and comprehensive analysis of cell-surface markers to study human lung mast cell heterogeneity has yet to be performed., Methods: Human lung mast cells were obtained from lung lobectomies, and the expression of 332 cell-surface markers was analyzed using flow cytometry and the LEGENDScreen™ kit. Markers that exhibited high variance were selected for additional analyses to reveal whether they were correlated and whether discrete mast cell subpopulations were discernable., Results: We identified the expression of 102 surface markers on human lung mast cells, 23 previously not described on mast cells, of which several showed high continuous variation in their expression. Six of these markers were correlated: SUSD2, CD49a, CD326, CD34, CD66 and HLA-DR. The expression of these markers was also correlated with the size and granularity of mast cells. However, no marker produced an expression profile consistent with a bi- or multimodal distribution., Conclusions: LEGENDScreen analysis identified more than 100 cell-surface markers on mast cells, including 23 that, to the best of our knowledge, have not been previously described on human mast cells. The comprehensive expression profiling of the 332 surface markers did not identify distinct mast cell subpopulations. Instead, we demonstrate the continuous nature of human lung mast cell heterogeneity., Competing Interests: S-ED reports personal fees from AstraZeneca, Cayman Chemicals, GSK, Novartis, Regeneron, Sanofi, and Teva, for consultancies outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rönnberg, Boey, Ravindran, Säfholm, Orre, Al-Ameri, Adner, Dahlén, Dahlin and Nilsson.)

Systemic lupus erythematosus (SLE) is an autoimmune disease that attacks almost every organ. The condition mostly happens to adults but is also found in children, and the latter have the most severe manifestations. Among adults, females, especially non-Caucasian, are mostly affected. Even if the etiology of SLE remains unclear, studies show a close relation between this disease and both genetics and environment. Despite the large number of published articles about SLE, we still do not have a clear picture of its pathogenesis, and no specific drug has been found to treat this condition effectively. The implication of macrophages in SLE development is gaining ground, and studying it could answer these gaps. Indeed, both in vivo and in vitro studies increasingly report a strong link between this disease and macrophages. Hence, this review aims to explore the role of macrophages polarization and plasticity in SLE development. Understanding this role is of paramount importance because in-depth knowledge of the connection between macrophages and this systemic disease could clarify its pathogenesis and provide a foundation for macrophage-centered therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahamada, Jia and Wu.)

Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis to host defense and cancer. Eosinophils have been studied mostly in the context of Type 2 inflammatory responses such as those found in allergy. Nonetheless, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Recent data suggest that the pleotropic roles of eosinophils are due to heterogeneous responses to environmental cues. Despite this, the activation profile of eosinophils, in response to various stimuli is yet to be defined. To better understand the transcriptional spectrum of eosinophil activation, we exposed eosinophils to Type 1 (e.g. IFN-γ, E. coli ) vs. Type 2 (e.g. IL-4) conditions and subjected them to global RNA sequencing. Our analyses show that IL-4, IFN-γ, E. coli and IFN-γ in the presence of E. coli (IFN-γ/ E. coli )-stimulated eosinophils acquire distinct transcriptional profiles, which polarize them towards what we termed Type 1 and Type 2 eosinophils. Bioinformatics analyses using Gene Ontology based on biological processes revealed that different stimuli induced distinct pathways in eosinophils. These pathways were confirmed using functional assays by assessing cytokine/chemokine release (i.e. CXCL9, CCL24, TNF-α and IL-6) from eosinophils following activation. In addition, analysis of cell surface markers highlighted CD101 and CD274 as potential cell surface markers that distinguish between Type 1 and Type 2 eosinophils, respectively. Finally, the transcriptome signature of Type 1 eosinophils resembled that of eosinophils that were obtained from mice with experimental colitis whereas the transcriptome signature of Type 2 eosinophils resembled that of eosinophils from experimental asthma. Our data demonstrate that eosinophils are polarized to distinct "Type 1" and "Type 2" phenotypes following distinct stimulations. These findings provide fundamental knowledge regarding the heterogeneity of eosinophils and support the presence of transcriptional differences between Type 1 and Type 2 cells that are likely reflected by their pleotropic activities in diverse disease settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dolitzky, Shapira, Grisaru-Tal, Hazut, Avlas, Gordon, Itan, Shomron and Munitz.)

Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Ma, Gong, Guo, Fu, Zhang, Zhou and Li.)

Neutrophils are critical components of the body's immune response to infection, being loaded with a potent arsenal of toxic mediators and displaying immense destructive capacity. Given the potential of neutrophils to impart extensive tissue damage, it is perhaps not surprising that when augmented these cells are also implicated in the pathology of inflammatory diseases. Prominent neutrophilic inflammation is a hallmark feature of patients with chronic lung diseases such as chronic obstructive pulmonary disease, severe asthma, bronchiectasis and cystic fibrosis, with their numbers frequently associating with worse prognosis. Accordingly, it is anticipated that neutrophils are central to the pathology of these diseases and represent an attractive therapeutic target. However, in many instances, evidence directly linking neutrophils to the pathology of disease has remained somewhat circumstantial and strategies that have looked to reduce neutrophilic inflammation in the clinic have proved largely disappointing. We have classically viewed neutrophils as somewhat crude, terminally differentiated, insular and homogeneous protagonists of pathology. However, it is now clear that this does not do the neutrophil justice, and we now recognize that these cells exhibit heterogeneity, a pronounced awareness of the localized environment and a remarkable capacity to interact with and modulate the behaviour of a multitude of cells, even exhibiting anti-inflammatory, pro-resolving and pro-repair functions. In this review, we discuss evidence for the role of neutrophils in chronic lung disease and how our evolving view of these cells may impact upon our perceived assessment of their contribution to disease pathology and efforts to target them therapeutically., (© 2021 John Wiley & Sons Ltd.)

Th17 and Treg cells play an important role in regulating tissue inflammation and maintaining the stability of the immune system. They regulate inflammatory responses, participate in the occurrence and development of autoimmune diseases and tumors, and determine the disease progress. Malignant tumor is one of the diseases with the highest mortality rate in the world. However, the efficacy of traditional treatment is limited, so it is necessary to find safe and efficient treatment methods. Studies have shown that the balance of Th17/Treg cells plays a critical role in tumor progression. In this paper, we review the antitumor and tumor-suppressing effects of Th17/Treg cells, and new strategies for tumor therapy, combined with new research hotspots such as immune checkpoint therapy, miRNA-related gene therapy, and metabolic pathway regulation of Th17/Treg cell differentiation and tumor generation. The synergistic therapy is expected to be widely used in the future clinical practice, providing a new choice for the prevention and treatment of malignant tumors., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

When helper T (T H ) cell polarization was initially described three decades ago, the T H cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond T H 1 and T H 2 cells, this led to the coining of various T H 17 and regulatory (T reg ) cell subsets as well as T H 22, T H 25, follicular helper (T FH ), T H 3, T H 5 and T H 9 cells. High-dimensional single-cell analysis revealed that a categorization of T H cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of T H cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that T H cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying T H cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures T H cell plasticity and conversion as well as the breadth of immune responses in vivo., (© 2021. Springer Nature America, Inc.)

More than 100 years have passed since Elie Metchnikoff discovered macrophage. Over the recent decade, attracting information about macrophage polarization have been reported. This is because many molecules have been identified as markers of macrophage polarization. Additionally, mechanistic insights have been demonstrated by experiments with various stimuli-induced macrophage polarization. Historically and simply, macrophages are divided into M1 (classically activated) and M2 (alternatively activated). However, some of them are not specific yet. Studies in the field of cardiology revealed the plasticity of macrophages and their subsets are divided into details: Mhem, MHb, Mox and M4 macrophages. M2 macrophages were further divided in M2a, M2b, M2c and M2d. There appears to be more phenotypes of macrophages. However, there still lack studies in dermatological field. This review summarizes the spectrum of macrophage activation and finding about various roles of macrophages in the dermatological field., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4 + T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4 + FoxP3 + CD25 + regulatory T cells (Tregs) were known to suppress function of effector CD4 + T cells and contribute to resolution of disease. It has been recently reported that some CD4 + T-cell subsets demonstrate shared phenotypes with another CD4 + T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these 'plastic CD4 + T cells' are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

The monocyte/macrophage lineage cells were found involved in the pathogenesis of systemic sclerosis (SSc) disease. The naïve macrophages are activated either to M1 cells with proinflammatory roles or to M2 cells that function to resolve inflammation with tissue repair. Recently, cells with dual phenotypes were detected in SSc disease. So, we aimed in this study to demonstrate different monocyte/macrophage phenotypes in peripheral cells from a group of Egyptian SSc patients, correlating percentages of these cells with the clinical findings in patients. The study participants comprised 41 patients with diffuse cutaneous SSc disease and 25 healthy individuals as controls. Clinical, radiological, and laboratory tests were conducted for SSc patients. Different phenotypes of the monocyte/macrophage subsets were identified in peripheral blood of patients and controls by flow cytometry for characteristic M1 (CD80, CD86, and TLR4) and M2 (CD204, CD163 and CD206) markers. SSc patients showed higher percentages of peripheral cells of the M1, M2, and mixed M1/M2 phenotypes within the monocyte/macrophage lineage compared to controls. Different cell phenotypes were associated significantly with the disease duration, modified Rodnan's score, the Medsger skin score, and the Medsger lung in SSc patients. Some cells with the M1/M2 phenotypes were higher in SSc patients with pitting scars, arthritis, and myalgia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Tissue-resident memory T (T RM ) cells are non-recirculating cells that exist throughout the body. Although T RM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze T RM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T RM cell function, durability and malleability. We find that unequal responsiveness to TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103 - T RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-responsive CD103 + T RM counterparts. Furthermore, whereas CD103 - T RM cells readily modified their phenotype upon relocation, CD103 + T RM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for T RM cell development, tissue adaptation of these cells confers discrete functional properties such that T RM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5 + T-BET + memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8 + T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8 + T lymphocytes, while CD4 + T cells were less expanded and skewed toward T CM and T H 2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8 + GZMB + effector cells were clonally expanded both during the infection and post-infection, while CD8 + GZMK + lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8 + GZMB + and GZMK + subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8 + T cell population with memory precursor-like features., (Copyright © 2021, American Association for the Advancement of Science.)

Gamma-delta (γδ) T cells are a heterogeneous population of immune cells, which constitute <5% of total T cells in mice lymphoid tissue and human peripheral blood. However, they comprise a higher proportion of T cells in the epithelial and mucosal barrier, where they perform immune functions, help in tissue repair, and maintaining homeostasis. These tissues resident γδ T cells possess properties of innate and adaptive immune cells which enables them to perform a variety of functions during homeostasis and disease. Emerging data suggest the involvement of γδ T cells during transplant rejection and survival. Interestingly, several functions of γδ T cells can be modulated through their interaction with other immune cells. This review provides an overview of development, differentiation plasticity into regulatory and effector phenotypes of γδ T cells during homeostasis and various diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The presence of immune cells is a morphological hallmark of rapidly progressive glomerulonephritis, a disease group that includes anti-glomerular basement membrane glomerulonephritis, lupus nephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The cellular infiltrates include cells from both the innate and the adaptive immune responses. The latter includes CD4 + and CD8 + T cells. In the past, CD4 + T cell subsets were viewed as terminally differentiated lineages with limited flexibility. However, it is now clear that Th17 cells can in fact have a high degree of plasticity and convert, for example, into pro-inflammatory Th1 cells or anti-inflammatory Tr1 cells. Interestingly, Th17 cells in experimental GN display limited spontaneous plasticity. Here we review the literature of CD4 + T cell plasticity focusing on immune-mediated kidney disease. We point out the key findings of the past decade, in particular that targeting pathogenic Th17 cells by anti-CD3 injection can be a tool to modulate the CD4 + T cell response. This anti-CD3 treatment can trigger a regulatory phenotype in Th17 cells and transdifferentiation of Th17 cells into immunosuppressive IL-10-expressing Tr1 cells (Tr1exTh17 cells). Thus, targeting Th17 cell plasticity could be envisaged as a new therapeutic approach in patients with glomerulonephritis., (© 2021. The Author(s).)

Adipose tissue macrophages (ATMs) regulate homeostasis and contribute to the metabolically harmful chronic inflammation in obese individuals. While evident heterogeneity of resident ATMs has been described previously, their phenotype, developmental origin, and functionality remain inconsistent. We analyzed white adipose tissue (WAT) during homeostasis and diet interventions using comprehensive and unbiased single-cell mass cytometry and genetic lineage tracking models. We now provide a uniform definition of individual subsets of resident ATMs. We show that in lean mice, WAT co-harbors eight kinetically evolving CD206 + macrophage subpopulations (defined by TIM4, CD163, and MHC II) and two CD206 - macrophage subpopulations. TIM4 - CD163 + , TIM4 - CD163 - and CD206 - macrophage populations are largely bone marrow-derived, while the proliferating TIM4 + CD163 + subpopulation is of embryonic origin. All macrophage subtypes are active in phagocytosis, endocytosis, and antigen processing in vitro , whereas TIM4 + CD163 + cells are superior in scavenging in vivo . A high-fat diet induces massive infiltration of CD206 - macrophages and selective down-regulation of MHC II on TIM4 + macrophages. These changes are reversed by dietary intervention. Thus, the developmental origin and environment jointly regulate the functional malleability of resident ATMs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Félix, Jokela, Karhula, Kotaja, Savontaus, Salmi and Rantakari.)

Background: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent., Objective: We sought to investigate the role of CYLD in Treg cell function and T H 2 cell immune responses under steady-state conditions and during helminth infection., Methods: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays., Results: Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation., Conclusions: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into T H 2 cell-like effector cells, which potentiates parasite resistance., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Effective treatment of osteoarthritis (OA) remains a huge clinical challenge despite major research efforts. Different tissues and cell-types within the joint contribute to disease pathogenesis, and there is great heterogeneity between patients in terms of clinical features, genetic characteristics and responses to treatment. Inflammation and the most abundant immune cell type within the joint, macrophages, have now been recognised as possible players in disease development and progression. Here we discuss recent findings on the involvement of synovial inflammation and particularly the role of synovial macrophages in OA pathogenesis. Understanding macrophage involvement may hold the key for improved OA treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thomson and Hilkens.)

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1 + Ly6C hi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1 + Ly6C hi monocytes into naïve mice promoted lung metastasis in the mice. Ym1 + Ly6C hi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1 + Ly6C hi -monocyte-promoted lung metastasis. These findings indicate that Ym1 + Ly6C hi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shibuya, Kamiyama, Sawada, Kikuchi, Maruyama, Sawado, Ikeda, Asano, Kurotaki, Tamura, Yoneda, Imada, Satoh, Akira, Tanaka and Yotsumoto.)

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feng, Chen, Ni, Little, Xu, Tang and Weng.)

The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4 + T cell-intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive-memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.

Fusobacterium nucleatum ( Fn ) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (M φ ) was involved in CRC progress driven by Fn infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of Fn in M φ polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of M φ into the M2-like M φ phenotype by in vitro study. Histological observation from Fn -positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like M φ . Fn -induced M2-like M φ polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn -challenged M φ and CRC cells. In addition, Fn -challenged M2-like M φ conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics in vitro and significantly enhanced tumor growth in vivo , all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF- κ B signaling pathway mediated Fn -induced S100A9 expression and subsequent M2-like M φ activation. Collectively, these findings indicate that elevated S100A9 in Fn -infected CRC microenvironment participates in M2-like M φ polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF- κ B/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn -associated CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Liu, Kong, Wu, Peng, Zhang, Zhou and Duan.)

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C + monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wen, Yan, Wang and Liu.)

Background: Excessive alcohol intake is associated with adverse immune response-related effects, however, acute and chronic abuse differently modulate monocyte activation. In this study, we have evaluated the phenotypic and functional changes of monocytes in acutely intoxicated healthy volunteers (HV)., Methods: Twenty-two HV consumed individually adjusted amounts of alcoholic beverages until reaching a blood alcohol level of 1‰ after 4h (T4). Peripheral blood was withdrawn before and 2h (T2), 4h (T4), 6h (T6), 24h (T24), and 48h (T48) after starting the experiment and stained for CD14, CD16 and TLR4. CD14 bright CD16 - , CD14 bright CD16 + and CD14 dim CD16 + monocyte subsets and their TLR4 expression were analyzed by flow cytometry. Inflammasome activation via caspase-1 in CD14 + monocytes was measured upon an ex vivo in vitro LPS stimulation. Systemic IL-1β and adhesion capacity of isolated CD14 + monocytes upon LPS stimulation were evaluated., Results: The percentage of CD14 + monocyte did not change following alcohol intoxication, whereas CD14 bright CD16 - monocyte subset significantly increased at T2 and T24, CD14 bright CD16 + at T2, T4 and T6 and CD14 dim CD16 + at T4 and T6. The relative fraction of TLR4 expressing CD14 + monocytes as well as the density of TLR4 surface presentation increased at T2 and decreased at T48 significantly. TLR4 + CD14 + monocytes were significantly enhanced in all subsets at T2. TLR4 expression significantly decreased in CD14 bright CD16 - at T48, in CD14 bright CD16 + at T24 and T48, increased in CD14 dim CD16 + at T2. IL-1β release upon LPS stimulation decreased at T48, correlating with TLR4 receptor expression. Alcohol downregulated inflammasome activation following ex vivo in vitro stimulation with LPS between T2 and T48 vs . T0. The adhesion capacity of CD14 + monocytes decreased from T2 with significance at T4, T6 and T48. Following LPS administration, a significant reduction of adhesion was observed at T4 and T6., Conclusions: Alcohol intoxication immediately redistributes monocyte subsets toward the pro-inflammatory phenotype with their subsequent differentiation into the anti-inflammatory phenotype. This is paralleled by a significant functional depression, suggesting an alcohol-induced time-dependent hyporesponsiveness of monocytes to pathogenic triggers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Janicova, Haag, Xu, Garza, Dunay, Neunaber, Nowak, Cavalli, Marzi, Sturm and Relja.)

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.

Macrophages are phagocytic cells with essential participation in immunological events of the oral cavity. However, the role of these cells in oral lichen planus (OLP) and oral lichenoid lesions (OLL) remains unclear. The present study aimed to evaluate the density of macrophages in OLP and OLL, and to compare it with that of oral inflammatory fibrous hyperplasia (OIFH) (control group). 14 cases of OLP, 14 cases of OLL and 14 cases of OIFH were selected for immunohistochemical analysis of CD68 + (M1) and CD163 + (M2) macrophage expression. CD68 + and CD163 + macrophages densities were measured in the intraepithelial and subepithelial areas. The statistical tests used were multivariate analysis of variance, as well as a correlation and linear regression. OLP has more CD68+ macrophages when comparing with OLL (p = 0.001) and OIFH (p = 0.045). There is a very strong relationship between the macrophages types (p < 0.0001) in OLP and OLL. The linear regression showed that to OLL development (p < 0.0001/R 2'  = 0.9584), the presence of different types of macrophages are more essential than to OLP (p < 0.0001/R 2'  = 0.8983). However, in the OLP these dependencies are also largely. CD68 + macrophages may be associated with immunopathogenesis of OLP, indicating a pro-inflammatory activity and regulatory role in the type of T-cell response. Besides, CD68 + macrophages can cooperate in the diagnosis of OLP. These results are essential to future studies that seek a therapeutic target for OLP and OLL., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is the most devastating progressive interstitial lung disease that remains refractory to treatment. Pathogenesis of IPF relies on the aberrant cross-talk between injured alveolar cells and myofibroblasts, which ultimately leads to an aberrant fibrous reaction. The contribution of the immune system to IPF remains not fully explored. Recent evidence suggests that both innate and adaptive immune responses may participate in the fibrotic process. Dendritic cells (DCs) are the most potent professional antigen-presenting cells that bridge innate and adaptive immunity. Also, they exert a crucial role in the immune surveillance of the lung, where they are strategically placed in the airway epithelium and interstitium. Immature DCs accumulate in the IPF lung close to areas of epithelial hyperplasia and fibrosis. Conversely, mature DCs are concentrated in well-organized lymphoid follicles along with T and B cells and bronchoalveolar lavage of IPF patients. We have recently shown that all sub-types of peripheral blood DCs (including conventional and plasmacytoid DCs) are severely depleted in therapy naïve IPF patients. Also, the low frequency of conventional CD1c + DCs is predictive of a worse prognosis. The purpose of this mini-review is to focus on the main evidence on DC involvement in IPF pathogenesis. Unanswered questions and opportunities for future research ranging from a better understanding of their contribution to diagnosis and prognosis to personalized DC-based therapies will be explored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bocchino, Zanotta, Capitelli and Galati.)

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8 -/- ), with increased IL-6 levels in nTregs from CD8 -/- mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8 -/- mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8 -/- compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8 -/- mice. The predominant GT repeat in CD8 -/- nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis.

Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (T EM ) cells, central memory T (T CM ) cells, and tissue-resident memory T (T RM ) cells have been identified. The most recently identified subset, T RM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. T RM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, T RM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8 + T RM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4 + T RM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4 + T RM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4 + T RM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4 + T RM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hirahara, Kokubo, Aoki, Kiuchi and Nakayama.)