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Nature Communications Dec 2021Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to...
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.
Topics: Adenocarcinoma; Animals; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Communication; Cell Line, Tumor; Cell Proliferation; Granulocyte-Macrophage Colony-Stimulating Factor; Immunosuppression Therapy; Inflammation; Macrophages; Male; Mice, Inbred C57BL; Neoplasm Metastasis; Oncostatin M; Pancreatic Neoplasms; Pancreatic Stellate Cells; Receptors, Oncostatin M; Signal Transduction; Tumor Microenvironment; Mice
PubMed: 34921158
DOI: 10.1038/s41467-021-27607-8 -
Science Advances Apr 2023CD34 cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional...
CD34 cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional role of these cells in the ischemic muscle microenvironment. Here, we combined the single-cell RNA sequencing and genetic lineage tracing technology, then provided exact single-cell atlases of normal and ischemic limb tissues in human and mouse, and consequently found that bone marrow (BM)-derived macrophages with antigen-presenting function migrated to the ischemic site, while resident macrophages underwent apoptosis. The macrophage oncostatin M (OSM) regulatory pathway was specifically turned on by ischemia. Simultaneously, BM CD34-derived proregenerative fibroblasts were recruited to the ischemia niche, where they received macrophage-released OSM and promoted angiopoietin-like protein-associated angiogenesis. These findings provided mechanisms on the cellular events and cell-cell communications during tissue ischemia and regeneration and provided evidence that CD34 cells serve as fibroblast progenitors promoting tissue regeneration.
Topics: Humans; Mice; Animals; Oncostatin M; Signal Transduction; Ischemia; Macrophages; Fibroblasts
PubMed: 37043578
DOI: 10.1126/sciadv.add2632 -
Journal For Immunotherapy of Cancer Mar 2021Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma...
BACKGROUND
Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.
METHODS
We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.
RESULTS
The spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.
CONCLUSIONS
TANs and TAMs interact to promote ICC progression by activating STAT3.
Topics: Animals; Bile Duct Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Coculture Techniques; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Interleukin-11; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neutrophils; Oncostatin M; Phosphorylation; STAT3 Transcription Factor; Signal Transduction; Tumor Microenvironment; Tumor-Associated Macrophages; Mice
PubMed: 33692217
DOI: 10.1136/jitc-2020-001946 -
Gut Feb 2023The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma...
OBJECTIVE
The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.
DESIGN
Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, ; ; mice (KPC) and the ; mice (KC) were crossed with allele floxed mice ( ) or conditional overexpressing mice (R26 ) to generate KPCL2 or KCL2 and KPCL2 or KCL2 mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.
RESULTS
Using these PDAC mouse models, we show that while ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects and expression and collagen fibre alignment.
CONCLUSION
Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.
Topics: Humans; Mice; Animals; Epithelial-Mesenchymal Transition; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Macrophages; Amino Acid Oxidoreductases
PubMed: 35428659
DOI: 10.1136/gutjnl-2021-325564 -
Science (New York, N.Y.) Sep 2020Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2... (Comparative Study)
Comparative Study
Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Cytokines; DNA, Bacterial; Dendritic Cells; Female; Flow Cytometry; HLA-DR Antigens; Humans; Immunity; Immunity, Innate; Immunoglobulins; Inflammation Mediators; Interferon Type I; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Myeloid Cells; Pandemics; Pneumonia, Viral; SARS-CoV-2; Signal Transduction; Single-Cell Analysis; Systems Biology; TOR Serine-Threonine Kinases; Transcription, Genetic; Transcriptome
PubMed: 32788292
DOI: 10.1126/science.abc6261 -
Bone Research Mar 2021Alveolar bone is the thickened ridge of jaw bone that supports teeth. It is subject to constant occlusal force and pathogens invasion, and is therefore under active bone...
Alveolar bone is the thickened ridge of jaw bone that supports teeth. It is subject to constant occlusal force and pathogens invasion, and is therefore under active bone remodeling and immunomodulation. Alveolar bone holds a distinct niche from long bone considering their different developmental origin and postnatal remodeling pattern. However, a systematic explanation of alveolar bone at single-cell level is still lacking. Here, we construct a single-cell atlas of mouse mandibular alveolar bone through single-cell RNA sequencing (scRNA-seq). A more active immune microenvironment is identified in alveolar bone, with a higher proportion of mature immune cells than in long bone. Among all immune cell populations, the monocyte/macrophage subpopulation most actively interacts with mesenchymal stem cells (MSCs) subpopulation. Alveolar bone monocytes/macrophages express a higher level of Oncostatin M (Osm) compared to long bone, which promotes osteogenic differentiation and inhibits adipogenic differentiation of MSCs. In summary, our study reveals a unique immune microenvironment of alveolar bone, which may provide a more precise immune-modulatory target for therapeutic treatment of oral diseases.
PubMed: 33723232
DOI: 10.1038/s41413-021-00141-5 -
Autophagy Feb 2021The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was...
The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was positively correlated with psoriatic severity in patients and mouse models and could be inhibited by mitogen-activated protein kinase (MAPK) family inactivation. The impairment of autophagic flux alleviated psoriasisform inflammation. We also found that an autophagy-based unconventional secretory pathway (autosecretion) dependent on ATG5 (autophagy related 5) and GORASP2 (golgi reassembly stacking protein 2) promoted psoriasiform KC inflammation. Moreover, the alarmin HMGB1 (high mobility group box 1) was more effective than other autosecretory proteins in regulating psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs eliminated the differences in psoriasiform inflammation between KCs and KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in KCs . These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inflammation. Finally, we demonstrated that mice displayed attenuated psoriatic inflammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis. 3-MA: 3-methyladenine; ACTB: actin beta; AGER: advanced glycosylation end-product specific receptor; Anti-HMGB1: anti-HMGB1 neutralizing antibody; Anti-IL18: anti-IL18 neutralizing antibody; Anti-IL1B: anti-IL1B neutralizing antibody; ATG5: autophagy related 5; BAF: bafilomycin A; BECN1: beclin 1; CASP1: caspase 1; CCL: C-C motif chemokine ligand; CsA: cyclosporine A; ctrl shRNA: lentivirus harboring shRNA against control; CXCL: C-X-C motif chemokine ligand; DCs: dendritic cells; DMEM: dulbecco's modified Eagle's medium; ELISA: enzyme-linked immunosorbent assay; EM: electron microscopy; FBS: fetal bovine serum; shRNA: lentivirus harboring shRNA against ; GORASP2/GRASP55: golgi reassembly stacking protein 2; GR1: a composite epitope between LY6 (lymphocyte antigen 6 complex) locus C1 and LY6 locus G6D antigens; H&E: hematoxylin and eosin; HMGB1: high mobility group box 1; shRNA: lentivirus harboring shRNA against ; IFNG/IFN-γ: interferon gamma; IL17A: interleukin 17A; IL18: interleukin 18; IL1A/IL-1α: interleukin 1 alpha; IL1B/IL-1β: interleukin 1 beta; IL22/IL-22: interleukin 22; IL23A: interleukin 23 subunit alpha; IL23R: interleukin 23 receptor; IMQ: imiquimod; ITGAM/CD11B: integrin subunit alpha M; ITGAX/CD11C: integrin subunit alpha X; IVL: involucrin; KC: keratinocyte; KD: knockdown; KO: knockout; mice: mice bearing an allele, in which exon 3 of the gene is flanked by two loxP sites; : mice bearing an flox allele, in which exon 2 to 4 of the gene is flanked by two loxP sites; mice: keratinocyte-specific knockout mice generated by mating mice with mice expressing recombinase under the control of the promoter of mice: keratinocyte-specific knockout mice generated by mating mice with mice expressing recombinase under the control of the promoter of mice: mice expressing 164-amino acid splice variant recombinase under the control of promoter of ; LAMP1: lysosomal associated membrane protein 1; LDH: lactate dehydrogenase; LORICRIN: loricrin cornified envelope precursor protein; M5: TNF, IL1A, IL17A, IL22 and OSM in combination; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MKI67: marker of proliferation Ki-67; MTT: thiazolyl blue tetrazolium bromide; NFKB/NF-κB: nuclear factor kappa B; NHEKs: primary normal human epidermal keratinocytes; NS: not significant; OSM: oncostatin M; PASI: psoriasis area and severity index; PtdIns3K: class III phosphatidylinositol 3-kinase; qRT-PCR: quantitative RT-PCR; RELA/p65: RELA proto-oncogene, NF-kB subunit; rHMGB1: recombinant HMGB1; rIL18: recombinant interleukin 18; rIL1B: recombinant interleukin 1 beta; S100A: S100 calcium binding protein A; SQSTM1/p62: sequestosome 1; T17: IL17A-producing T; TCR: T-cell receptor; KO mice: (T cell receptor delta chain) knockout mice, which show deficient receptor expression in all adult lymphoid and epithelial organs; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor; WOR: wortmannin; WT: wild-type; γδT17 cells: IL17A-producing γδ T cells.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; HMGB1 Protein; Inflammation; Interleukin-1beta; Keratinocytes; Mice, Transgenic; NF-kappa B; Proto-Oncogene Mas
PubMed: 32019420
DOI: 10.1080/15548627.2020.1725381 -
Journal of Clinical Medicine Apr 2021Skin inflammation often evokes pruritus, which is the major subjective symptom in many inflammatory skin diseases such as atopic dermatitis and prurigo nodularis.... (Review)
Review
Skin inflammation often evokes pruritus, which is the major subjective symptom in many inflammatory skin diseases such as atopic dermatitis and prurigo nodularis. Pruritus or itch is a specific sensation found only in the skin. Recent studies have stressed the pivotal role played by interleukin-31 (IL-31) in the sensation of pruritus. IL-31 is produced by various cells including T helper 2 cells, macrophages, dendritic cells and eosinophils. IL-31 signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor β. Recent clinical trials have shown that the anti-IL-31RA antibody nemolizumab can successfully decrease pruritus in patients with atopic dermatitis and prurigo nodularis. The IL-31 pathway and pruritic skin are highlighted in this review article.
PubMed: 33924978
DOI: 10.3390/jcm10091906 -
Biomaterials Dec 2022Osteoimmunology is at full display during endosseous implant osseointegration. Bone formation, maintenance and resorption at the implant surface is a result of... (Review)
Review
Osteoimmunology is at full display during endosseous implant osseointegration. Bone formation, maintenance and resorption at the implant surface is a result of bidirectional and dynamic reciprocal communication between the bone and immune cells that extends beyond the well-defined osteoblast-osteoclast signaling. Implant surface topography informs adherent progenitor and immune cell function and their cross-talk to modulate the process of bone accrual. Integrating titanium surface engineering with the principles of immunology is utilized to harness the power of immune system to improve osseointegration in healthy and diseased microenvironments. This review summarizes current information regarding immune cell-titanium implant surface interactions and places these events in the context of surface-mediated immunomodulation and bone regeneration. A mechanistic approach is directed in demonstrating the central role of osteoimmunology in the process of osseointegration and exploring how regulation of immune cell function at the implant-bone interface may be used in future control of clinical therapies. The process of peri-implant bone loss is also informed by immunomodulation at the implant surface. How surface topography is exploited to prevent osteoclastogenesis is considered herein with respect to peri-implant inflammation, osteoclastic precursor-surface interactions, and the upstream/downstream effects of surface topography on immune and progenitor cell function.
Topics: Osseointegration; Titanium; Surface Properties; Osteogenesis; Immunomodulation
PubMed: 36410109
DOI: 10.1016/j.biomaterials.2022.121903 -
Frontiers in Immunology 2023Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13,...
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRβ and IL31RA subunits, and OSMRβ can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients.
OBJECTIVE
The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression.
METHODS
The expression levels of the OSM gene () and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes.
RESULTS
We confirmed overexpression of in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG.
CONCLUSION
These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.
Topics: Humans; Mice; Animals; Oncostatin M; Interleukin-4; Ganglia, Spinal; Interleukin-13; Pruritus; Interleukins; Dermatitis, Atopic; Receptors, Interleukin; Psoriasis
PubMed: 38035099
DOI: 10.3389/fimmu.2023.1251031