ImmunoHorizons最新文献_第2页

NRF2 agonists 4-octyl-itaconate and dimethyl fumarate reduce human and bovine RSV proliferation and RSV disease in a murine model. NRF2激动剂4-辛酯-衣康酸酯和富马酸二甲酯在小鼠模型中减少人和牛RSV增殖和RSV疾病。

ImmunoHorizons Pub Date : 2025-08-25 DOI: 10.1093/immhor/vlaf036

Fabian E Diaz, Jodi L McGill

{"title":"NRF2 agonists 4-octyl-itaconate and dimethyl fumarate reduce human and bovine RSV proliferation and RSV disease in a murine model.","authors":"Fabian E Diaz, Jodi L McGill","doi":"10.1093/immhor/vlaf036","DOIUrl":"https://doi.org/10.1093/immhor/vlaf036","url":null,"abstract":"Human and bovine respiratory syncytial virus (RSV) are significant causes of morbidity and mortality in human and cattle populations worldwide, respectively. RSV disease is characterized by deleterious inflammatory immune responses as well as generation of radical oxygen species in the airways. Recent reports have shown antiviral and anti-inflammatory activity of NRF2 agonists and immunometabolite derivatives 4-octyl-itaconate (4-OI) and dimethyl fumarate (DMF), suggesting their potential to protect against viral-induced inflammation. Here, we evaluated whether 4-OI or DMF impact human and bovine RSV replication and its associated inflammatory response in vitro and the efficacy of these NRF2 agonists in preventing RSV disease in a murine model. We observed that 4-OI and DMF inhibited the early inflammatory response to RSV as well as reduced infectious titers in epithelial cells. Moreover, mice treated with 4-OI or DMF were partially protected against RSV-induced weight loss and airway inflammation and showed reduced viral loads and interleukin-6 levels in the lung. Overall, these results support the use of NRF2 agonists 4-OI and DMF in the prevention of RSV disease in target populations.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of conserved T cell epitopes and flanking amino acid mutants of endogenous retrovirus Gag antigen in nonobese diabetic mice. 非肥胖糖尿病小鼠内源性逆转录病毒Gag抗原保守T细胞表位和侧翼氨基酸突变体的鉴定。

ImmunoHorizons Pub Date : 2025-08-25 DOI: 10.1093/immhor/vlaf033

Yang D Dai, Shuhui Li, Amanda Margosiak, Wen-Yuan Hu

{"title":"Identification of conserved T cell epitopes and flanking amino acid mutants of endogenous retrovirus Gag antigen in nonobese diabetic mice.","authors":"Yang D Dai, Shuhui Li, Amanda Margosiak, Wen-Yuan Hu","doi":"10.1093/immhor/vlaf033","DOIUrl":"https://doi.org/10.1093/immhor/vlaf033","url":null,"abstract":"The interactions between endogenous retroviruses (ERVs) and major histocompatibility complex molecules may significantly influence autoimmune diseases due to their common roles in the evolution and development of the adaptive immune system. Notably, regions within the Gag antigens of a specific group of ERVs, similar to murine leukemia retroviruses, exhibit patterns of sequence conservation, variation, and mutation. One highly conserved peptide of Gag, p5-13 (VTTPLSLTL), binds with high affinity to a nonclassic major histocompatibility complex molecule, Qa-1, and is preferentially recognized by T cells enriched in the pancreas of nonobese diabetic (NOD) mice, which spontaneously develop autoimmune type 1 diabetes. Interestingly, deep sequencing analysis of the Gag genes expressed in NOD mice has revealed numerous mutations flanking the conserved Qa-1-binding sequences. This includes 1 epitope, p310-328, which contains both conserved and mutated residues that can elicit autoreactive T cells in NOD mice. A specific residue, D316, within this epitope accumulates multiple mutations as the disease progresses, leading to a reduction in the consensus score in sequence alignment at this position during the later stages of prediabetes. Consistently, the substitution of the D316 residue with a dominant mutant, G316, enhances the antigenicity of this epitope, stimulating autoreactive T cells in prediabetic NOD mice to release interferon-γ . Thus, sequence variants of ERV Gag antigens encode overlapping conserved and highly mutated epitopes that can be recognized by T cells and utilized for biomarker discovery.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring MHC class II I-Ab blockade as a potential treatment for Sjögren's disease in the mouse model. 在小鼠模型中探索MHC II类I-Ab阻断作为Sjögren病的潜在治疗方法

ImmunoHorizons Pub Date : 2025-08-25 DOI: 10.1093/immhor/vlaf030

Alexandria Voigt, Shivai Gupta, Yiran Shen, Patricia Glenton, Danmeng Li, David Ostrov, I Bhattacharyya, Cuong Q Nguyen

{"title":"Exploring MHC class II I-Ab blockade as a potential treatment for Sjögren's disease in the mouse model.","authors":"Alexandria Voigt, Shivai Gupta, Yiran Shen, Patricia Glenton, Danmeng Li, David Ostrov, I Bhattacharyya, Cuong Q Nguyen","doi":"10.1093/immhor/vlaf030","DOIUrl":"https://doi.org/10.1093/immhor/vlaf030","url":null,"abstract":"Sjögren's disease (SjD) is a chronic autoimmune disorder predominantly affecting females, characterized by exocrine gland dysfunction. This study investigates the therapeutic potential of 2-chloro-1-(4-hydroxy-phenyl)-ethanone (CHPE) and metformin in the C57BL/6.NOD-Aec1Aec2 mouse model, which closely mirrors human SjD. Molecular docking identified CHPE and metformin as high-affinity binders to the MHC class II I-Ab antigen-binding groove, suggesting their ability to inhibit antigen presentation and modulate immune responses. In-vitro assays confirmed their effectiveness in reducing T cell activation. In-vivo studies demonstrated that both preventative and therapeutic regimens of CHPE and metformin significantly reduced lymphocytic infiltration in the lacrimal glands, with metformin showing a more pronounced effect in females. Salivary gland infiltration was less responsive, though some reduction in focal scores was observed in male mice treated preventatively with CHPE. Both drugs altered the composition of lymphocytic infiltrates, particularly by reducing B cell populations, with notable sex-specific differences in response to treatment. CHPE and metformin also reduced anti-nuclear antibody levels, with CHPE showing stronger effects in females. Additionally, both drugs improved saliva and tear secretion, with metformin being more effective in the preventative regimen, especially in females. T cell receptor transductant assays revealed that CHPE and metformin exert their therapeutic effects through antigen-specific pathways, inhibiting T cell responses to SjD-associated autoantigens. Overall, this study provides compelling evidence that CHPE and metformin can modulate immune responses and improve gland function, with effectiveness varying by sex and age. These findings support the potential of these compounds as personalized treatments for SjD tailored to individual patient characteristics.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Maturation of thymocytes with a monoclonal TCR under control of Trac promoter elements in the absence of β-selection. 在没有β选择的情况下，Trac启动子元件控制单克隆TCR胸腺细胞成熟。

ImmunoHorizons Pub Date : 2025-07-15 DOI: 10.1093/immhor/vlaf035

Alexander K Tsai, Eduardo Cruz-Hinojoza, Madeline A Ellefson, Adam L Burrack, Brandon M Larsen, Ryan J Martinez, Ingunn M Stromnes

{"title":"Maturation of thymocytes with a monoclonal TCR under control of Trac promoter elements in the absence of β-selection.","authors":"Alexander K Tsai, Eduardo Cruz-Hinojoza, Madeline A Ellefson, Adam L Burrack, Brandon M Larsen, Ryan J Martinez, Ingunn M Stromnes","doi":"10.1093/immhor/vlaf035","DOIUrl":"10.1093/immhor/vlaf035","url":null,"abstract":"Thymocyte maturation is a tightly controlled and sequential process of T cell receptor (TCR) gene rearrangement that generates a broad repertoire of T cells with minimal self-reactivity. We previously generated TCR exchange (TRex) mice by targeting a mesothelin-specific \"1045\" TCR to the Trac locus in murine zygotes. While 1045 T cells from TRex mice display physiological development and function, some T cells coexpress endogenous TCRβ chains, suggesting that β-selection is required for 1045 T cell development. Here, we evaluate thymocyte maturation in the setting of compromised β-selection by deleting endogenous Tcrb or Rag2 in TRex mice. T cells readily form in TRex mice lacking Tcrb, though thymocytes mature through developmental trajectories that appear dependent on interleukin-7 and γδTCR. In contrast, mature T cells fail to form in the absence of Rag2. Maturation of αβ thymocytes bypassing β-selection is reduced by 100-fold, in part because γδTCR+ precursors are biased to form conventional γδ T cells. Nevertheless, in TRex mice, these unconventional β-selection-independent trajectories yield a mature αβ T cell population with uniform TCR expression and pronounced function.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aberrant humoral immune responses and intestinal homeostasis in Cd38 Bst1 double knockout mice. Cd38 Bst1双敲除小鼠的异常体液免疫反应和肠道稳态。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf029

Ayano Yahagi, Masanori Iseki, Keisuke Yaku, Takashi Nakagawa, Motoyuki Itoh, Tomoyuki Mukai, Katsuhiko Ishihara

{"title":"Aberrant humoral immune responses and intestinal homeostasis in Cd38 Bst1 double knockout mice.","authors":"Ayano Yahagi, Masanori Iseki, Keisuke Yaku, Takashi Nakagawa, Motoyuki Itoh, Tomoyuki Mukai, Katsuhiko Ishihara","doi":"10.1093/immhor/vlaf029","DOIUrl":"10.1093/immhor/vlaf029","url":null,"abstract":"Bone marrow stromal cell antigen-1 (BST-1)/CD157 and CD38 are ectoenzymes belonging to the mammalian ADP-ribosyl cyclase family. Previous analyses of BST-1-deficient mice (Bst1KO) in a 129×C57BL/6J(B6) mixed background revealed that BST-1 is a positive regulator of humoral immunity. Murine BST-1 has recently been known to be an enteroneuroimmune regulator. To further clarify the functions of the ADP-ribosyl cyclase family in vivo, in this study, we generated CD38 and BST-1 double knockout mice (Cd38Bst1DKO) and compared them with Cd38KO, Bst1KO, and wild-type (WT) mice in B6 backgrounds. Flow cytometry analyses of the spleen revealed a decrease in B cells in Cd38KO mice, an increase in marginal zone (MZ) B cells of Bst1KO, and a decrease in neutrophils in Cd38Bst1DKO mice. Compared with WT mice, Cd38Bst1DKO mice showed decreased basal serum immunoglobulins and antigen-specific antibodies in memory responses to a thymus-dependent antigen. Because BST-1 is selectively expressed on WT MZ B cells responsive to lipopolysaccharide, enhanced antibody production in Bst1KO and increased growth responses of Bst1KO B cells to lipopolysaccharide stimulation suggest a suppressive role for BST-1 in Toll-like receptor 4 signaling in MZ B cells. Additionally, aged Cd38Bst1DKO mice displayed enlarged mesenteric lymph nodes and elongated small intestine; these phenotypes appeared only in Cd38Bst1DKO and not in Cd38KO or Bst1KO mice, indicating a cooperative role of CD38 and BST-1 in intestinal homeostasis regulation. Overall, these findings indicate the involvement of ADP-ribosyl cyclases CD38 and BST-1 in regulating humoral immune responses and small intestine homeostasis.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deficiency of interleukin-1 receptor antagonist aggravates Citrobacter rodentium infection in mice. 白细胞介素-1受体拮抗剂缺乏可加重小鼠啮齿柠檬酸杆菌感染。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf034

Beng San Yeoh, Piu Saha, Vinita Kushwaha, Amira F Gohara, Matam Vijay-Kumar

{"title":"Deficiency of interleukin-1 receptor antagonist aggravates Citrobacter rodentium infection in mice.","authors":"Beng San Yeoh, Piu Saha, Vinita Kushwaha, Amira F Gohara, Matam Vijay-Kumar","doi":"10.1093/immhor/vlaf034","DOIUrl":"10.1093/immhor/vlaf034","url":null,"abstract":"The interleukin-1 receptor (IL-1R) plays an important role in mediating the inflammatory responses against pathogens. However, it is not clear whether a sustained IL-1R signaling following the loss of its endogenous inhibitor, IL-1R antagonist (IL-1RA), could improve mucosal immunity against the murine enteropathogen, Citrobacter rodentium. At basal levels, IL-1RA-deficient (IL1raKO) mice displayed an elevated inflammatory tone as indicated by their higher levels of circulating neutrophils, and the inflammatory marker, lipocalin-2, in both systemic and luminal contents. We reasoned that the heightened inflammatory tone of IL1raKO mice may be beneficial in clearing C. rodentium efficiently, but such was not the case. Oral challenge of C. rodentium (1 × 109 colony-forming units/mouse) resulted in luminal colonization, which peaked at day 7 postinfection, in both wild-type and IL1raKO mice. However, IL1raKO mice displayed a higher C. rodentium burden, and exacerbated colonic inflammation and hyperplasia. The aggravated infection in IL1raKO mice was corroborated using in vivo imaging of mice infected with a bioluminescent strain of C. rodentium. However, IL1raKO mice do not display any defect in their neutrophils with respect to their recruitment to the inflamed gut, generation of neutrophil extracellular traps and reactive oxygen species, or their ability to kill C. rodentium in vitro. In contrast, the macrophages of IL1raKO mice were able to upregulate more inducible nitric oxide synthase and produce more nitrite that wild-type macrophages; however, the former was less effective in mediating killing of C. rodentium in vitro. Together, our results suggest that IL-1RA plays a protective role in combating enteropathogen infection.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Influenza A virus disruption of dendritic cell-natural killer cell crosstalk impacts activation of naïve helper and cytotoxic T cell subsets. 甲型流感病毒破坏树突状细胞-自然杀伤细胞串扰影响naïve辅助细胞和细胞毒性T细胞亚群的激活。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf024

Connor A Morson, Chandana K Uppalapati, Brina S Lopez, Lisa M Kronstad

{"title":"Influenza A virus disruption of dendritic cell-natural killer cell crosstalk impacts activation of naïve helper and cytotoxic T cell subsets.","authors":"Connor A Morson, Chandana K Uppalapati, Brina S Lopez, Lisa M Kronstad","doi":"10.1093/immhor/vlaf024","DOIUrl":"10.1093/immhor/vlaf024","url":null,"abstract":"Dendritic cells (DCs) and natural killer (NK) cells engage in reciprocal interactions to trigger an efficient innate immune response while governing downstream adaptive immunity. Here, we used an ex vivo autologous human primary immune cell coculture system of DCs and NK cells to examine their impact on naïve CD4+ and CD8+ T cell (CD3+CD45RA+CD197+) activation in response to influenza A viral (IAV) infection. Using multiparameter flow cytometry, we observed that culturing T cells with both DCs and NK cells enhanced CD69 expression on CD4+ and CD8+ T cells, increased CD25 on CD4+ T cells, and promoted CD8+ T cell proliferation, compared with cultures with only NK cells or DCs. When DCs were exposed to the pandemic A/California/07/2009 (H1N1) strain or the A/Victoria/361/2011 (H3N2) strain, subsequent coculture with NK cells reduced the frequency of CD4+CD69+ and CD8+CD69+ naïve T cells. Notably, H3N2, but not H1N1, exposure also reduced CD4+CD25+ T cell frequencies. The IAV-mediated curtailment of T cell activation was dependent on viral replication because exposure to DCs with irradiated the H1N1 strain followed increased the frequency of CD4+CD69+, CD8+CD69+, CD4+CD25+, and CD8+CD25+ T cells, while irradiation of H3N2 increased the frequency of CD4+CD69+, CD8+CD69+ and proliferation of CD4+ and CD8+ T cells. These findings demonstrate that IAV can partially subvert DC-NK cell crosstalk to impair naïve T cell activation in a strain-dependent manner. This knowledge may guide the design of next-generation influenza vaccines to elicit robust cellular immune responses.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of extensive diversity in immunoglobulin light chain variable germline genes across biomedically important mouse strains. 免疫球蛋白轻链可变种系基因在生物医学上重要小鼠品系中的广泛多样性。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf031

Justin T Kos, Yana Safonova, Kaitlyn Shields, Catherine A Silver, William D Lees, Andrew M Collins, Corey T Watson

{"title":"Characterization of extensive diversity in immunoglobulin light chain variable germline genes across biomedically important mouse strains.","authors":"Justin T Kos, Yana Safonova, Kaitlyn Shields, Catherine A Silver, William D Lees, Andrew M Collins, Corey T Watson","doi":"10.1093/immhor/vlaf031","DOIUrl":"10.1093/immhor/vlaf031","url":null,"abstract":"The light chain immunoglobulin (IG) genes of inbred mouse strains are poorly documented in current gene databases. We previously showed that IG heavy chain (IGH) loci of wild-derived mouse strains, representing the major mouse subspecies, contained 247 IGH variable (V) sequences not curated in the International ImMunoGeneTics (IMGT) information system database, commonly used for adaptive immune receptor repertoire sequencing (AIRR-seq) analysis. Despite containing levels of polymorphism similar to the IGH locus, the germline gene content and diversity of the light chain loci (kappa, IGK; lambda, IGL) have not been comprehensively cataloged. To explore the extent of germline light chain repertoire diversity across mouse strains commonly used in the biomedical sciences, we performed AIRR-seq analysis and germline gene inference for 18 inbred mouse strains, including 4 wild-derived strains with diverse sub-species origins. We inferred 1582 IGKV and 63 IGLV sequences, representing 459 and 22 unique IGKV and IGLV germline alleles. Of the unique germline IGKV and IGLV sequences, 67.8% and 59%, respectively, were undocumented in IMGT. Across strains we observed germline IGKV sequences shared by three distinct IGK haplotypes and a more conserved IGLV germline repertoire. In addition, joining (J) gene inference indicated a novel IGKJ2 allele shared between PWD/PhJ and MSM/MsJ, a novel IGLJ1 allele for LEWES/EiJ, and a novel IGLJ2 allele for MSM/MsJ. Finally, combined IGHV, IGKV, and IGLV phylogenetic analysis of wild-derived germline sets revealed reduced diversity for light chain sequences compared to the heavy chain, suggesting potential evolutionary differences between heavy and light chain loci.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interleukin-27-producing cells in gram-negative neonatal sepsis display diverse phenotypes and functions in the liver. 革兰氏阴性新生儿败血症中产生白细胞介素27的细胞在肝脏中表现出不同的表型和功能。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf026

Jordan K Vance, Nathalie Lailler, Ashley M Divens, Jessica M Povroznik, Madhavi Annamanedi, Kathleen M Brundage, Cory M Robinson

{"title":"Interleukin-27-producing cells in gram-negative neonatal sepsis display diverse phenotypes and functions in the liver.","authors":"Jordan K Vance, Nathalie Lailler, Ashley M Divens, Jessica M Povroznik, Madhavi Annamanedi, Kathleen M Brundage, Cory M Robinson","doi":"10.1093/immhor/vlaf026","DOIUrl":"10.1093/immhor/vlaf026","url":null,"abstract":"Neonates have increased vulnerability to life-threatening infections due to the distinct immune landscape. Interleukin (IL)-27 is a key component of this immune profile that we have previously shown to be elevated in both newborn humans and mice. IL-27 continues to increase in the serum and tissues consistent with poor outcomes during gram-negative neonatal bacterial sepsis. Presently, we dissected the IL-27 producer profile at a single-cell level using IL-27p28eGFP reporter mice in our previously established model of neonatal sepsis with luciferase-expressing K1-encapsulated Escherichia coli. Whole animal imaging regionally highlighted the spleen, liver, and lungs as key infection sites by bacterial luminescence. Flow cytometry showed that IL-27 producers increased significantly in the liver with infection and were predominantly F4/80+ and CD11b+ with subpopulations that emerged expressing additional markers. This information paired with single-cell RNA sequencing further identified the most robust populations as monocytes, monocyte-derived cells, and Kupffer cells followed by smaller populations of dendritic cells and neutrophils. The transcriptome demonstrated a diverse range of functionality amongst populations that included differential expression of genes implicated in bactericidal, metabolic, and inflammatory changes. Collectively, the transcriptome of IL-27 producers from the livers of infected animals suggests an uncoordinated mix of inflammatory and suppressive activity that may contribute to immune dysregulation characteristic of sepsis. Together, this work provides previously undescribed insight into the details of IL-27 producers during early-life infection. This further provides essential information needed to support IL-27 as a therapeutic target for neonatal bacterial sepsis.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages. 外源性精氨酸对巨噬细胞炎症细胞因子和诱导型一氧化氮合酶表达的调控存在差异。

ImmunoHorizons Pub Date : 2025-07-14 DOI: 10.1093/immhor/vlaf028

Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther

{"title":"Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages.","authors":"Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther","doi":"10.1093/immhor/vlaf028","DOIUrl":"10.1093/immhor/vlaf028","url":null,"abstract":"Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is unclear but it is crucial to consider amino acid restoration as a tool for treating sepsis. We demonstrate that lipopolysaccharide (LPS)-mediated iNOS, ASS1, and ASL protein expression and nitric oxide generation were dependent on exogenous arginine in RAW 264.7 macrophages. Exogenous citrulline was not sufficient to restore nitric oxide generation in arginine-free conditions. Despite the induction of iNOS and ASS1 mRNA in arginine-free conditions, exogenous arginine was necessary and citrulline was not sufficient to overcome eIF2-α (elongation initiation factor 2-α)-mediated translational repression of iNOS and ASS1 protein expression. Moreover, exogenous arginine, but not citrulline, selectively modified the inflammatory cytokine and chemokine expression profile of the LPS-activated RAW 264.7 and bone marrow-derived macrophages. Our study highlights the complex, differential regulation of proinflammatory cytokine expression, and NO generation by exogenous arginine in macrophages.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0