Immuno, Volume 2, Issue 1 (March 2022) – 16 articles

In the past few years, a renowned interest in the interplay between the immune system and central nervous systems (CNS) has sparked a wealth of new experimental studies. Two recent publications in Science shed new light on the “resident” immune cell populations in the CNS and their functions in homeostasis and pathological status, with potential implications in understanding CNS disease mechanisms and in designing new “intelligent” therapies. Full article

Leishmaniasis is a zoonotic and vector-borne infectious disease that is caused by the genus Leishmania belonging to the trypanosomatid family. The protozoan parasite has a digenetic life cycle involving a mammalian host and an insect vector. Leishmaniasisis is a worldwide public health problem falling under the neglected tropical disease category, with over 90 endemic countries, and approximately 1 million new cases and 20,000 deaths annually. Leishmania infection can progress toward the development of species–specific pathologic disorders, ranging in severity from self-healing cutaneous lesions to disseminating muco-cutaneous and fatal visceral manifestations. The severity and the outcome of leishmaniasis is determined by the parasite’s antigenic epitope characteristics, the vector physiology, and most importantly, the immune response and immune status of the host. This review examines the nature of host–pathogen interaction in leishmaniasis, innate and adaptive immune responses, and various strategies that have been employed for vaccine development. Full article

Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis. Full article

This review summarizes recent progress in understanding the pathogenesis of IgG4-related disease (IgG4-RD), with a focus on fibrosis. Several studies reported that CD4⁺ T cells with cytotoxic activity promoted by the secretion of granzyme and perforin, cytotoxic CD4⁺ T cells (CD4⁺CTLs), and disease-specific activated B cells, infiltrated inflamed tissues and cooperated to induce tissue fibrosis in autoimmune fibrotic diseases such as IgG4-RD, systemic sclerosis, and fibrosing mediastinitis. An accumulation of cells undergoing apoptotic cell death induced by CD4⁺CTLs and CD8⁺CTLs followed by macrophage-mediated clearing and finally tissue remodeling driven by cytokines released by CD4⁺CTLs, activated B cells, and M2 macrophages may contribute to the activation of fibroblasts and collagen production. In IgG4-RD, this process likely involves the apoptosis of non-immune, non-endothelial cells of mesenchymal origin and subsequent tissue remodeling. In summary, CD4⁺CTLs infiltrate affected tissues where they may cooperate with activated B cells, CD8⁺CTLs, and M2 macrophages, to induce apoptosis by secreting cytotoxic cytokines. These immune cells also drive fibrosis by secreting pro-fibrotic molecules in IgG4-RD. Full article

Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Here, we review the role of autophagy in virus infection, focusing on both pro-viral and anti-viral host responses using a select group of viruses. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. Some of these mechanisms are also covered in our review. Lastly, we conclude with the thought that autophagy can be targeted for therapeutic interventions against viral diseases. Full article

Nigella sativa, Conyza bonariensis, and Alchemilla vulgaris are highly recommended in Greco-Arab traditional medicine as anti-hemorrhoid medicinal plants. The efficacy and safety of a topical cream (HPC) consisting of water–ethanol extracts of these three plants were evaluated here in vitro and in a randomized, double-blind, placebo-controlled study (RDBPC). HPC showed no significant cytotoxic effects in fibroblast cell line 3T3 (LDH-release and MTT assay); it inhibited the nitric oxide production by cultured monocyte cell line THP-1 in a dose-dependent manner (reaching the control levels of untreated cells at a concentration of 100 μg/mL). HPC showed a dose-dependent antibacterial activity against Escherichia coli (60% inhibition compared to Ampicillin at 5 mg/disc) and a significant vasoconstriction effect on intestinal vein rings (40% increase compared to phenylephrine). In a RDBPC with 77 hemorrhoidal disease (patients ages 19–61 years with a median grade of hemorrhoids of 2.0), we determined the anti-hemorrhoid efficacy and safety of HPC. The patients were randomly assigned to the HPC group (54 patients) or the placebo group (23 patients). They were asked to apply 2–3 mL of HPC or placebo twice daily for 6 days. The degree of hemorrhoidal disease severity, hemorrhage severity, pain, and itching served as an evaluation of the HPC efficacy. Compared to the placebo group, the obtained results showed that 6 days of treatment with HPC reduced the indexes of hemorrhage severity, severity of pain, and severity of itching to 0–1, 1, and 1 after 6 days, respectively. In conclusion, patients treated with HPC had a significant clinical improvement in all disease severity parameters compared to placebo. In vitro evaluations proved HPC to have significant antimicrobial, anti-inflammatory, and vasoconstriction effects. Therefore, HPC represents an interesting alternative treatment for hemorrhoidal disease. Full article

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. This clinically heterogeneous neurological disorder is closely related to Guillain–Barré syndrome and is considered the chronic counterpart of that acute disease. Currently available treatments are mostly empirical; they include corticosteroids, intravenous immunoglobulins, plasma exchange and chronic immunosuppressive agents, either alone or in combination. Recent advances in the understanding of the underlying pathogenic mechanisms in CIDP have brought a number of novel ways of possible intervention for use in CIDP. This review summarizes selected pre-clinical and clinical findings, highlights the importance of using adapted animal models to evaluate the efficacy of novel treatments, and proposes the outlines of future directions to ameliorate the conditions of patients with CIDP. Full article

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however, the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that knockdown or overexpression of miR-511-3p inversely correlates with PPARγ mRNA levels and affects its transcriptional activity following treatment with rosiglitazone (RSG; PPARγ agonist), in the presence or absence of LPS. Additionally, we show that PPARγ-mediated suppression of DC activation and pro-inflammatory cytokine production in miR-511-3p knockdown DCs is abrogated following overexpression of miR-511-3p. Lastly, PPARγ activation suppressed LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. Our data thus suggests that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases. Full article

Polymorphonuclear neutrophils (PMN) are the most abundant leucocytes in the circulation in humans. They represent a heterogeneous population exerting diverse functions through several activities. Usually described as typical pro-inflammatory cells, immunomodulatory properties of PMNs have been reported. Among others, once activated and depending on the stimulus, PMNs expel neutrophil extracellular traps (NET) in the extracellular space. NETs are complexes made of DNA and granule proteins representing an innate immune mechanism fighting infections. Nevertheless, an excess of NET formation might be involved in the development of inflammatory or autoimmune responses. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two chronic, inflammatory, autoimmune diseases of unknown etiology and affecting mostly women. Several abnormal or non-classical functions of PMNs or PMN sub-populations have been described in SLE and RA. Particularly, NETs have been suggested to trigger pro-inflammatory responses by exposing pro-inflammatory mediators. Likewise, NETs may be the targets of autoantibodies or even might trigger the development of autoantibodies by exposing autoantigens. In the present review, we will summarize heterogeneous properties of human PMNs and we will discuss recent evidence linking PMNs and NETs to the pathogenesis of both SLE and RA. Full article

Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Despite the critical role of PD-L1 in various types of cancers, the regulatory mechanism of PD-L1 expression on the cell surface of PDAC is poorly understood. Therefore, uncovering potential modulators of cell surface localisation of PD-L1 may provide a new strategy to improve ICB therapy in patients with PDAC. Here, we examined the role of ezrin/radixin/moesin (ERM) family scaffold proteins that crosslink transmembrane proteins with the actin cytoskeleton in the surface localisation of PD-L1 in KP-2 cells, a human PDAC cell line. Our results demonstrated the abundant protein expression of PD-L1, ezrin, and radixin, but not moesin, as well as their colocalisation in the plasma membrane. Interestingly, immunoprecipitation analysis detected the molecular interaction of PD-L1 with ezrin and radixin. Moreover, gene silencing of ezrin moderately decreased the mRNA and cell surface expression of PD-L1, while that of radixin greatly decreased the surface expression of PD-L1 without altering the mRNA levels. Thus, radixin and ezrin differentially modulate the cell surface localisation of PD-L1 in KP-2 cells, highlighting a potential therapeutic target to improve the current ICB therapy in PDAC. Full article

NK cells have usually been defined as cells of the innate immune system, although they are also involved in adaptative responses. These cells belong to the innate lymphocyte cells (ILC) family. They remove unwanted cells, tumoral cells and pathogens. NK cells are essential for viral infection clearance and are involved in tolerogenic responses depending on the dynamic balance of the repertoire of activating and inhibitory receptors. NK plasticity is crucial for tissue function and vigilant immune responses. They directly eliminate virus-infected cells by recognising viral protein antigens using a non-MHC dependent mechanism, recognising viral glycan structures and antigens by NCR family receptors, inducing apoptosis by Fas-Fas ligand interaction, and killing cells by antibody-dependent cell cytotoxicity via the FcγIII receptor. Activating receptors are responsible for the clearance of virally infected cells, while inhibitory KIR receptor activation impairs NK responses and facilitates virus escape. Effective NK memory cells have been described and characterised by a low NKG2A and high NKG2C or NKG2D expression. NK cells have also been used in cell therapy. In SARS-CoV-2 infection, several contradicting reports about the role of NK cells have been published. A careful analysis of the current data and possible implications will be discussed. Full article

Improvements in bioengineering methodology and tools have allowed for significant progress in the development of therapeutics and diagnostics in medicine, as well as progress in many other diverse industries, such as materials manufacturing, food and agriculture, and consumer goods. Glioblastomas present significant challenges to adequate treatment, in part due to their immune-evasive and manipulative nature. Rational-design bioengineering using novel scaffolds, biomaterials, and inspiration across disciplines can push the boundaries in treatment development to create effective therapeutics for glioblastomas. In this review, we will discuss bioengineering strategies currently applied across diseases and disciplines to inspire creative development for GBM immunotherapies. Full article

Although exercise-induced humoral factors known as exerkines benefit systemic health, the role of most exerkines has not been investigated. Monocyte chemoattractant protein-1 (MCP-1) is a representative chemokine whose circulating concentrations increase after exercise, and it is one of the exerkines. MCP-1 is a ligand for CC chemokine receptor 2 (CCR2), which is expressed on monocytes, macrophages, and muscle cells. However, there is no information on the role of CCR2 signaling in exercise. Therefore, to investigate the research question, we administrated CCR2 antagonist or PBS to mice to inhibit CCR2 signaling before and after exercise. Our results showed that CCR2 signaling inhibition promoted exercise-induced macrophage infiltration and inflammation 24 h after exercise in muscle. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in muscle. However, neutrophil infiltration and oxidative stress had no contribution to exercise-induced inflammation by CCR2 signaling inhibition. CCR2 signaling inhibition also exacerbated exercise-induced inflammation immediately after exercise in kidney, liver, and adipose tissues. To summarize, pharmacological inhibition of CCR2 signaling exacerbated exercise-induced inflammation independently of neutrophil infiltration and oxidative stress. Full article

Activation of the nod-like receptor protein 3 (NLRP3) leads to the release of the proinflammatory cytokine IL-1β, which then facilitates pathogen control by macrophages. The role of NLRPs in controlling infection of epithelial cells is not well understood. Our hypothesis was that activation of the NLRP3 inflammasome in colonic epithelial cells would promote macrophage-mediated epithelial recovery after infection with the pathogen Citrobacter rodentium. We devised a co-culture model using mouse colonic epithelial cells (CMT-93) and macrophages (J774A.1) during infection with C. rodentium. Inflammasome was activated using LPS and ATP and inhibited by YVAD. We assessed cytokine secretion (ELISA), macrophage recruitment and pathogen penetration (immunofluorescence), and epithelial barrier integrity (transepithelial electrical resistance). Macrophages were recruited to the apical membrane of epithelial cells, associated with tight junctions, promoted epithelial barrier recovery, and displaced C. rodentium. While NLRP3 was expressed in infected epithelial cells, IL-18 or IL-1β secretion remained unchanged. Supernatants from infected epithelial cells promoted infection clearance by macrophage; while this was inflammasome-independent, ATP significantly improved epithelial barrier recovery. The inflammasome appears to promote epithelial barrier function, independent of IL-18 and IL-1β secretion. Inflammasome activation in macrophages plays a dual role of promoting pathogen clearance and improving epithelial barrier integrity. Full article

Active vitamin D is a true steroid hormone with pleiotropic biological effects that go beyond the classical concept of bone metabolism regulation. In fact, adequate serum levels of 25-hydroxyvitamin D (>40 ng/mL) are required to support several biological functions, including the control of innate and adaptive immunity in course of infectious, inflammatory and autoimmune diseases. SARS-CoV-2 is responsible for the COVID-19 pandemic and deficient/insufficient serum levels of 25-hydroxyvitamin D are reported in very large cohorts of patients. Of note, vitamin D is involved in different pathophysiological processes, such as expression of SARS-CoV-2 receptor (ACE2), activation of innate (neutrophils with their extracellular traps, monocytes/macrophages, dendritic cells, natural killer cells) and adaptive (T and B lymphocytes) immune cells and clinical manifestations, such as coagulation/thrombotic disorders and acute respiratory distress syndrome. Randomized clinical trials regarding vitamin D supplementation in COVID-19 patients have shown favorable effects on the control of inflammation markers, arterial oxygen saturation/inspired fraction of oxygen ratio, admission to hospital intensive care units and mortality. A target of serum 25-hydroxyvitamin D > 50 ng/mL has been identified as protective for the course of COVID-19, potentially playing an ancillary role in the treatment of the disease. Full article