Programmed cell death plays a relevant role in the pathogenesis of visceral Leishmaniasis. Apoptosis selects suitable parasites, regulating parasite density, whereas autophagy eliminates pathogens. This study aimed to assess the inflammation and apoptosis in inflammatory cells and presents a unique description of the presence of autophagic and apoptotic Leishmania amastigotes in naturally Leishmania-infected dogs. Fragments from seemingly undamaged ear skin of sixteen Leishmania-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. Leishmania amastigotes were present on seemingly undamaged ear skin only in clinically affected dogs. Parasite load, morphometrical parameters of inflammation and apoptotic index of inflammatory cells were higher in clinically affected animals and were related to clinical manifestations. Apoptotic index and morphometric parameters of the inflammatory infiltrate in undamaged ear skin were positively correlated with parasite load. Apoptotic and non-apoptotic Leishmania amastigotes were observed within neutrophils and macrophages. Leishmania amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in Leishmania amastigotes were observed only in phagocytes of clinically affected dogs. Positive correlations were found between histomorphometry and clinical manifestations. Our results showed that apoptosis and autophagy in Leishmania amastigotes may be related to both the increase in parasite load and apoptotic index in inflammatory cells, and with the intensity of the inflammatory response in clinically affected dogs. Thus, our study suggests that apoptotic and autophagy Leishmania within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of Leishmania infection.

The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.

Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) in vitro modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.

Dermal and pulmonary fibrosis are the main clinical symptoms of systemic scleroderma (SSc), for which there are no effective therapeutic agents. Tocilizumab is thought to improve the symptoms of fibrosis, but the effect of tocilizumab on dermal fibrosis has not been explored. This study aims to investigate the therapeutic effect of tocilizumab on skin fibrosis by inhibiting CD38 macrophages in the bleomycin-induced SSc mice model.

Gastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC.

Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.

Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and RORγt and a downregulation in GATA3 and RORα. The mRNA levels of ILC related cytokines- IFNγ and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFNγ, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.

Conventional treatments for autoimmune uveitis, such as corticosteroids and systemic immunosuppressants, often result in adverse side effects, prompting the need for therapies targeting specific molecular pathways. This study investigates the effects of Arctiin, known for its diverse biological properties, on experimental autoimmune uveitis (EAU) through its action on Th17 cells and the JAK/STAT signaling pathway. Our findings reveal that Arctiin significantly alleviates EAU by reducing clinical scores, inflammatory cell infiltration, and levels of inflammatory cytokines like IL-17 and TNF-α in the eye. Arctiin achieves this by activating adiponectin receptor 1 (AdipoR1), which modulates the JAK/STAT pathway, thereby inhibiting Th17 cell differentiation and cytokine secretion. Additionally, Arctiin effectively suppresses IRBP-specific Th17 cell activation in cervical lymph nodes, further mitigating retinal inflammation and tissue damage. These results underscore Arctiin's potential as a therapeutic agent for uveitis and other autoimmune inflammatory disorders through the modulation of the AdipoR1/JAK/STAT pathway in Th17 cells.

Non-small cell lung cancer (NSCLC) remains one of the most prevalent and deadly malignancies. Despite advancements in molecular therapies and diagnostic methods, the 5-year survival rate for lung adenocarcinoma patients remains unacceptably low, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, a distinct form of regulated cell death, has emerged as a promising target in cancer treatment. This study investigates the role of TMEM164, a membrane protein, in promoting ferroptosis and modulating anti-tumor immunity in NSCLC, aiming to elucidate its therapeutic potential.

The peritoneal cavity (PerC) is a discrete anatomical compartment housing diverse peritoneal macrophage subpopulations. Nonetheless, there exists a paucity of knowledge concerning the distinct functions of these subpopulations in the context of hepatocellular carcinoma (HCC) and their evolution throughout tumor advancement. This investigation seeks to analyze the characteristics of two principal peritoneal macrophage subpopulations, specifically large peritoneal macrophage (LPM) and small peritoneal macrophage (SPM), in the context of HCC. The results of our research indicate a significant decrease in the proportion of LPM during the progression of HCC, accompanied by an increase in the quantity of SPM. Furthermore, SPM found in ascites exhibited a macrophage phenotype that supports tumor growth in HCC. Importantly, the dynamic decrease of LPM in murine models following lipopolysaccharide (LPS) stimulation led to a decrease in survival rate, highlighting the critical role of the altered LPM to SPM ratio in HCC survival. By employing clodronate liposomes (CL) to deplete peritoneal macrophage in murine models, followed by the adoptive transfer of LPM, we effectively prolonged the survival of HCC and attenuated tumor progression. Our results suggest that a decrease in the LPM to SPM ratio correlates with increased mortality in the HCC model. On the contrary, the maintenance of a high ratio of LPM to SPM has shown a positive effect on HCC survival. These findings have enhanced our understanding of the complex interaction between different subpopulations of peritoneal macrophage in the development of HCC. Furthermore, these results have important implications for the development of novel therapeutic strategies.

Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.

Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the in vivo cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA, IgACD22 (p < 0.001), and IgACD138 (p = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA B-cells through a T-cell-independent pathway.

Neurological disorders are the leading cause of disability worldwide, with Parkinson's disease (PD) emerging as a rapidly growing neurological condition on a global scale. Although treatments exist to alleviate symptoms and maintain patients' quality of life, PD remains incurable. According to some recent studies, natural killer (NK) cells may play a role in clearing alpha-synuclein aggregates, which are the main component of Lewy bodies that cause neuronal degeneration in Parkinson's disease. NK cells may also have an adverse impact on this condition by modulating inflammation and antigen-presenting cell function. Modifying NK cells derived from diverse sources, such as umbilical cord blood, presents a promising avenue for immunotherapy in PD patients, particularly during the early stages of the condition. Consequently, further research is essential to elucidate the mechanisms by which NK cells operate in Parkinson's patients and to assess their viability as potential biomarkers or therapeutic targets.

We previously reported that Tim-3, an immune checkpoint inhibitor, inhibits MHC-II expression, but the molecular mechanisms involved and the implications for antiviral immunity remain to be determined. Here, we found that during H1N1 infection, Tim-3 inhibits MHC-II expression in macrophages/microglia in vitro. Tim-3 interacts with MHC-II via its intracellular tail and induces proteasomal dependent degradation of MHC-II. In H1N1 infected macrophages/microglia, Tim-3 promotes the K48-linked ubiquitination of MHC-II via MARCH8, a ubiquitin E3 ligase that can be upregulated by Tim-3. In H1N1 infected mice, specific knockout of Tim-3 in macrophages leads to a decreased viral load, attenuates tissue damage and increases the survival rate. We have thus identified a novel mechanism by which Tim-3 mediates virus immune escape. Manipulating the Tim-3-MHC-II signaling pathway may provide a novel treatment for viral infections.

Galectins, glycan-binding proteins, have been identified as critical regulators of the immune system. Recently, Galectin-9 (Gal-9) has emerged as biomarker that correlates with disease severity in a range of inflammatory conditions. However, Gal-9 has highly different roles in the context of immunoregulation, with the potential to either stimulate or suppress the immune response. Neutralizing antibodies targeting Gal-9 have been developed and are in early test phase investigating their therapeutic potential in cancer. Despite ongoing research, the mechanisms behind Gal-9 action remain not fully understood, and extrapolating the implications of targeting this molecule from previous studies is challenging. Here, we examine the pleiotropic function of Gal-9 focusing on conventional T lymphocytes, providing a current overview of its immunostimulatory and immunosuppressive roles. In particular, we highlight that Gal-9 differentially regulates immune responses depending on the context. Considering this complexity, further investigation of Gal-9's intricate biology is necessary to define therapeutic strategies in immune disorders and cancer treatment aimed at inducing or inhibiting Gal-9 signaling.

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease characterized mainly by inflammatory changes in the intestinal mucosa. While the specific etiology of UC remains unclear, it is generally believed that it is related to many factors, among which the imbalance in the expression of molecules involved in pro-inflammatory and anti-inflammatory processes can lead to UC. CCL5 (C-C chemokine ligand 5) is one of the key pro-inflammatory factors and plays an indispensable role in various inflammatory diseases, including UC. CCL5 binds and activates the receptor CCR5 (C-C chemokine receptor type 5), which in turn, promotes signaling pathways such as PI3K/AKT, NF-κB, and Ras/MAPK, playing an important role in the pathogenesis of UC. The focus of this paper is on the function of the CCL5/CCR5 axis and its subsequent signaling pathways in UC therapy. In addition to this, the article further explores the possible healing benefits of CCR5 antagonists and agonists aimed at the CCL5/CCR5 axis for UC treatment.

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood forming around 15 % of all pediatric tumors. Despite advances in the treatment of NB, high-risk patients still face a grave prognosis. Adoptive cell therapies based on NK cells are becoming an assistive treatment for such cases. Moreover, there is also evidence that NKT-based therapies have promising results in the management of NB. Lower complications in comparison with adoptive T cell therapies, various cell sources, and miscellaneous tumor recognition mechanisms are some of the advantages of NK- and NKT-based therapies. This review is dedicated to searching for recent advances in this field.

Tumor-associated macrophages (TAM) is related to Ovarian cancer (OC) pathogenesis, but the exact mechanism remains unclear. This study investigated the expression of Kelch Domain Containing 8 A (KLHDC8A) in OC and the mechanism associated with TAM.

The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80 macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.

CD11c age-associated B cells (ABCs) have emerged as a key component in protective and autoreactive B cell responses. Lupus is an autoimmune disorder linked to reduced efficacy of vaccines and increased susceptibility to infections. Previously, we reported that excessive CD11c ABCs not only significantly contribute to autoantibody production but also promote aberrant T cell activation and compromised affinity-based germinal center selection in response to immunization in lupus mice. Yet, the regulation of CD11c ABC differentiation is not fully understood. In this study, we show that B cell-intrinsic IFN-γ is required for excessive CD11c ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting excessive CD11c ABC differentiation, which compromises affinity-based germinal center selection and affinity maturation in lupus, providing a potential strategy to normalize vaccine responses in lupus.

T helper 17 (Th17) cells play crucial roles in various autoimmune diseases, including ulcerative colitis (UC), which is characterized by widespread inflammation in the mucosa of the colon and rectum. To identify small-molecule compounds capable of inhibiting CD4 T cell differentiation into Th17 cells, we established a screening system. Through drug screening, we found that pyrrolidinedithiocarbamate ammonium (PDTC) effectively inhibits Th17 differentiation. In a dextran sulfate sodium (DSS)-induced UC mouse model, administration of PDTC significantly ameliorated colitis. PDTC treatment decreased the production of proinflammatory mediators and inhibited the proportion of Th17 cells in colitis-afflicted mice by suppressing NF-κB activation. These findings showed that PDTC can alleviate colitis by inhibiting NF-κB activation. The therapeutic effects of PDTC observed in a mouse model of UC provided a rationale for its application in clinical settings.