Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most prevalent cancer worldwide, significantly impacting patients' quality of life. Immune checkpoint inhibitors (ICI) have been employed in the treatment of recurrent/metastatic (R/M)-HNSCC patients. This meta-analysis aims to assess the efficacy and safety of durvalumab monotherapy compared to the combination of durvalumab and tremelimumab in R/M-HNSCC patients.

Billions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered and several cases of thrombocytopenia with thrombosis syndrome (TTS) have been reported after the administration of adenoviral vector vaccines. However, the effects of an inactivated COVID-19 vaccine, CoronaVac, on coagulation are not well understood.

Duck Tembusu virus (DTMUV), the causative agent of egg-drop syndrome, has caused substantial economic losses to duck industry. DTMUV infection leads to profound changes of host cells, including transcriptome and proteome. However, the lncRNA expression profile and the biological function of lncRNA have not been revealed. Therefore, DTMUV was used to inoculate duck embryo fibroblast cells (DEFs) for high-throughput RNA-sequencing (RNA-Seq). The results showed that 34 and 339 differently expressed lncRNAs were, respectively, identified at 12 and 24 h post-infection (hpi). To analyze their biological functions, target genes in cis were searched and the regulatory network was formed. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the target genes were strongly associated with immune system, signaling molecular and interaction, endocrine system, and signal transduction. The differently expressed lncRNAs were selected and verified by quantitative real-time polymerase chain reaction (RT-qPCR). Our study, for the first time, analyzed a comprehensive lncRNA expression profile in DEFs following DTMUV infection. The analysis provided a view on the important roles of lncRNAs in gene regulation and DTMUV infection.

Macrophages have a defensive function against bacteria through phagocytosis and the secretion of cytokines. Histone modifications play an essential role in macrophage functions. Here, we report that Cxxc finger protein 1 (CFP1), a key component of the SETD1 histone methyltransferase complex, promoted the phagocytic and bactericidal activity of GM-CSF-derived macrophages. CFP1-deficient mice were more susceptible to bacterial infection due to the decreased expression of Csf2rα, a subunit of the GM-CSF receptor essential for inflammation and alveolar macrophage development, through the loss of H3K4 modifications in the promoter of the Csf2rα gene. In addition, the lung tissues of CFP1-deficient mice exhibited spontaneous inflammatory symptoms, including both the infiltration of inflammatory cells and the accumulation of surfactant phospholipids and proteins. Furthermore, we showed that Csf2rα and PU.1 can partially rescue the defects in phagocytosis and in the intracellular killing of bacteria. Collectively, our data highlight the importance of CFP1 in the phagocytic and bactericidal activity of macrophages.

The Zika virus (ZIKV) epidemic poses a substantial threat to the public, and the development of safe and effective vaccines is a demanding challenge. In this study, we constructed a kind of self-assembling nanovaccine which confers complete protection against ZIKV infection. The ZIKV envelop protein domain III (zEDIII) was presented on recombinant human heavy chain ferritin (rHF) to form the zEDIII-rHF nanoparticle. Immunization of mice with zEDIII-rHF nanoparticle in the absence of an adjuvant induced robust humoral and cellular immune responses. zEDIII-rHF vaccination conferred complete protection against lethal infection with ZIKV and eliminated pathological symptoms in the brain. Importantly, the zEDIII-rHF nanovaccine induced immune response did not cross-react with dengue virus-2, overcoming the antibody-dependent enhancement (ADE) problem that is a safety concern for ZIKV vaccine development. Our constructed zEDIII-rHF nanovaccine, with superior protective performance and avoidance of ADE, provides an effective and safe vaccine candidate against ZIKV.

Multiple sclerosis (MS), an autoimmune and degenerative disease, is characterized by demyelination and chronic neuroinflammation. Bixin is a carotenoid isolated from the seeds of Bixa orellana that exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of bixin on MS have not yet been examined. To evaluate the effects and underlying molecular mechanisms of bixin on MS, experimental autoimmune encephalomyelitis (EAE) was established in C57BL/6 mice, which were treated via intragastric administration of bixin solutions. To evaluate the molecular mechanisms of bixin, quantitative reverse-transcription PCR, western blot, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assay analyses were performed. We found that bixin significantly improved the symptoms and pathology in EAE mice, reduced the release of inflammatory cytokines TNF-α, IL-6, IL-8, IL-17, and IFN-γ, and increased the expression of the anti-inflammatory cytokine IL-10. And bixin reduced the proportion of Th1 and Th17 cells in the spleen and CNS, and suppressed microglia aggregation, and TXNIP/NLRP3 inflammasome activity by scavenging excessive reactive oxygen species (ROS) in EAE mice. Furthermore, bixin inhibited inflammation and oxidative stress via activating nuclear factor erythroid 2-related factor 2 (NRF2), and its downstream genes in EAE mice, meanwhile, these effects were suppressed upon treatment with an NRF2 inhibitor, ML385. Bixin prevented neuroinflammation and demyelination in EAE mice primarily by scavenging ROS through activation of the NRF2 signaling pathway. Taken together, our results indicate that bixin is a promising therapeutic candidate for treatment of MS.

Atopic dermatitis (AD) is a recurrent chronic inflammatory skin disease affecting up to 30% of the children population, and immuno-regulatory therapy that could modify the course of disease is urgently needed. Probiotics have demonstrated therapeutic effects on AD and could potentially regulate the disease process. However, the efficacy of probiotics for AD is inconsistent among different studies, which is mainly due to the elusive mechanism and different species and (or) strains used. In this study, we designed a mixture of five strains of probiotics (named IW5) and analyzed the effect and mechanism of IW5 on calcipotriol (MC903)-induced AD-like dermatitis. We found that IW5 significantly alleviated skin inflammation of the MC903-induced AD in mice. Administration with IW5 induced increased production of regulatory T cells and regulatory dendritic cells (DCregs) in the mesenteric lymph nodes. We also found that the diversity of the gut microbiota in the mice with MC903-induced dermatitis was increased after IW5 administration, and the level of butyrate in the gut was elevated. In cell culture, butyrate induced the production of DCregs. Our study revealed the therapeutic effects of a newly designed probiotics mixture and uncovered a possible mechanism, providing a foundation for future clinical studies.

Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.

Although intratumoral chemoablation can obtain an impressive therapeutic effect, there is still incomplete ablation and tumor recurrence in some patients. This could be due to the short retention time of the drug in the tumor, the limited distribution of intratumoral drugs, and, beyond that, the immunotolerance caused by the tumor microenvironment (TME). There is still an urgent need to find an optimal drug sustained-release carrier and figure out the impact of regional injection to TME.

HPS1, a BLOC-3 subunit that acts as a guanine nucleotide exchange factor of Rab32/38, may play a role in the removal of VAMP7 during the maturation of large dense core vesicles of Paneth cells. Loss of HPS1 impairs lysozyme secretion and alters the composition of intestinal microbiota, which may explain the susceptibility of HPS-associated inflammatory bowel disease. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and other chronic organ lesions due to defects in tissue-specific lysosome-related organelles (LROs). For some HPS subtypes, such as HPS-1, it is common to have symptoms of HPS-associated inflammatory bowel disease (IBD). However, its underlying mechanism is largely unknown. HPS1 is a subunit of the BLOC-3 complex which functions in the biogenesis of LROs. Large dense core vesicles (LDCVs) in Paneth cells of the intestine are a type of LROs. We here first report the abnormal LDCV morphology (increased number and enlarged size) in HPS1-deficient pale ear (ep) mice. Similar to its role in melanosome maturation, HPS1 plays an important function in the removal of VAMP7 from LDCVs to promote the maturation of LDCVs. The immature LDCVs in ep mice are defective in regulated secretion of lysozyme, a key anti-microbial peptide in the intestine. We observed changes in the composition of intestinal microbiota in both HPS-1 patients and ep mice. These findings provide insights into the underlying mechanism of HPS-associated IBD development, which may be implicated in possible therapeutic intervention of this devastating condition.

Immune checkpoints such as programmed death-1 (PD-1) have been proven as antitumor targets by enhancing cytotoxic T cell activity. All immune checkpoint blockades are antibody therapeutics that have large size and high affinity, as well as known immune-related side effects and low responses. To overcome the limitation of antibody therapeutics, we have explored PD-1/PD-L1 (programmed death-ligand 1) blockades in traditional oriental medicine, which has a long history but has not yet studied PD-1/PD-L1 blockades. Sanguisorbae Radix extract (SRE) blocked PD-1 and PD-L1 binding in competitive ELISA. SRE effectively inhibited the PD-1/PD-L1 interaction, thereby improving T cell receptor (TCR) signaling and the NFAT-mediated luciferase activity of T cells. SRE treatment reduced tumor growth in the humanized PD-L1 MC38 cell allograft humanized PD-1 mouse model. Additionally, the combination of SRE and pembrolizumab (anti-PD-1 antibody) suppressed tumor growth and increased infiltrated cytotoxic T cells to a greater extent did either agent alone. This study showed that SRE alone has anticancer effects via PD-1/PD-L1 blockade and that the combination therapy of SRE and pembrolizumab has enhanced immuno-oncologic effects.

Giardia duodenalis is a zoonotic intestinal protozoan parasite that may cause host diarrhea and chronic gastroenteritis, resulting in great economic losses annually and representing a significant public health burden across the world. However, thus far, our knowledge on the pathogenesis of Giardia and the related host cell responses is still extensively limited. The aim of this study is to assess the role of endoplasmic reticulum (ER) stress in regulating G0/G1 cell cycle arrest and apoptosis during in vitro infection of intestinal epithelial cells (IECs) with Giardia. The results showed that the mRNA levels of ER chaperone proteins and ER-associated degradation genes were increased and the expression levels of the main unfolded protein response (UPR)-related proteins (GRP78, p-PERK, ATF4, CHOP, p-IRE1, XBP1s and ATF6) were increased upon Giardia exposure. In addition, cell cycle arrest was determined to be induced by UPR signaling pathways (IRE1, PERK and ATF6) through upregulation of p21 and p27 levels and promotion of E2F1-RB complex formation. Upregulation of p21 and p27 expression was shown to be related to Ufd1-Skp2 signaling. Therefore, the cell cycle arrest was induced by ER stress when infected with Giardia. Furthermore, the apoptosis of the host cell was also assessed after exposure to Giardia. The results indicated that apoptosis would be promoted by UPR signaling (PERK and ATF6), but would be suppressed by the hyperphosphorylation of AKT and hypophosphorylation of JNK that were modulated by IRE1 pathway. Taken together, both of the cell cycle arrest and apoptosis of IECs induced by Giardia exposure involved the activation of the UPR signaling. The findings of this study will deepen our understanding of the pathogenesis of Giardia and the associated regulatory network.

Interferon-gamma (IFN-γ), commonly referred to as type II interferon, is a crucial cytokine that coordinates the tumor immune process and has received considerable attention in tumor immunotherapy research. Previous studies have discussed the role and mechanisms associated with IFN-γ in specific tumors or diseases, but the relevant role of IFN-γ in pan-cancer remains uncertain.

Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype.

One rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear.

The initial infection and transmission of HIV-1 requires C-C chemokine receptor type 5 (CCR5). Here, we report that the membrane-proximal region (MPR, aa 22-38) of CCR5 participates in the infection of HIV-1. First, MPR-specific antibodies elicited in mice dose-dependently inhibited the infection of CCR5-tropic HIV-1. Second, substituting MPR with the same region from other co-receptors significantly impaired HIV-1 infection, while the key residues identified by alanine scanning mutagenesis formed an exposed leucine zipper-like structure. Moreover, a peptide derived from MPR could block the infection of a number of HIV-1 strains only before the formation of gp41 six-helix bundle, coincide with the early interaction between CCR5 and the gp120 protein during HIV-1 infection. These promising results ensured the potential of this previously uncharacterized domain as a starting point for the development of antiviral drugs, blocking antibodies, and HIV vaccines.

Microparticles (MPs, ~size between 0.1 and 1 mm) are lipid encased containers derived from intact cells which contain antigen from the parent cells. MPs are involved in intercellular communication and regulate inflammation. Stroke increases secretion of brain derived MP (BDMP) which activate macrophages/microglia and induce neuroinflammation. Lactadherin (Milk fat globule-EGF factor-8) binds to anionic phospholipids and extracellular matrices, promotes apoptotic cell clearance and limits pathogenic antigen cross presentation. In this study, we investigate whether BDMP affects stroke-induced neuroinflammation and whether Lactadherin treatment reduces stroke initiated BDMP-induced neuroinflammation, thereby improving functional outcome after stroke. Middle aged (8-9 months old) male C57BL/6J mice were subjected to distal middle cerebral artery occlusion (dMCAo) stroke, and BDMPs were extracted from ischemic brain 24 h after dMCAo by ultracentrifugation. Adult male C57BL/6J mice were subjected to dMCAo and treated via tail vein injection at 3 h after stroke with: (A) +PBS (n = 5/group); (B) +BDMPs (1.5 × 108, n = 6/group); (C) +Lactadherin (400 μg/kg, n = 5/group); (D) +BDMP+Lactadherin (n = 6/group). A battery of neurological function tests were performed and mice sacrificed for immunostaining at 14 days after stroke. Blood plasma was used for Western blot assay. Our data indicate: (1) treatment of Stroke with BDMP significantly increases lesion volume, neurological deficits, blood brain barrier (BBB) leakage, microglial activation, inflammatory cell infiltration (CD45, microglia/macrophages, and neutrophils) into brain, inflammatory factor (TNFα, IL6, and IL1β) expression in brain, increases axon/white matter (WM) damage identified by decreased axon and myelin density, and increases inflammatory factor expression in the plasma when compared to PBS treated stroke mice; (2) when compared to PBS and BDMP treated stroke mice, Lactadherin and BDMP+Lactadherin treatment significantly improves neurological outcome, and decreases lesion volume, BBB leakage, axon/WM injury, inflammatory cell infiltration and inflammatory factor expression in the ischemic brain, respectively. Lactadherin treatment significantly increases anti-inflammatory factor (IL10) expression in ischemic brain and decreases IL1β expression in plasma compared to PBS and BDMP treated stroke mice, respectively. BDMP increases neuroinflammation and aggravates ischemic brain damage after stroke. Thus, Lactadherin exerts anti-inflammatory effects and improves the clearance of MPs to reduce stroke and BDMP induced neurological deficits.

Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1β and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.

Although recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages.

A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly block the TYK2-mediated receptor-stimulated pathways by binding to the TYK2 JH2 domain and allosterically regulating the TYK2 JH1 kinase. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. Moreover, TYK2 JH2-binding ligands exhibit remarkable selectivity of TYK2 over JAK isoforms not only biochemically but also in a panel of receptor-stimulated JAK1/JAK2/JAK3-driven cellular functional assays. In addition, the TYK2 JH2-targeting ligands also demonstrate high selectivity in a multi-kinase screening panel. The data in the current study underscores that the TYK2 JH2 pseudokinase is a promising therapeutic target for achieving a high degree of biological selectivity. Meanwhile, targeting the JH2 domain represents an appealing strategy for the development of clinically well-tolerated TYK2 inhibitors that would have superior efficacy and a favorable safety profile compared to the existing Janus kinase inhibitors against autoimmune diseases.