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Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases in the world. It is characterized by recurrent eczematous lesions and intense itch, and many cytokines are involved in the pathogenesis of AD. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator. IL-31 is mainly produced by CD4+ helper T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the molecular mechanisms of how IL-31 is produced in helper T cells upon stimulation and transmits the itch sensation to the brain were largely unknown. Recently, by using original mouse models of AD, we have identified endothelial PAS domain 1 (EPAS1) and neurokinin B (NKB) as key molecules critical for IL-31 production and IL-31-mediated itch transmission, respectively. These molecules could be novel drug targets for AD-associated itch. This review highlights our recent findings, which show the functional significance of these molecules in the IL-31-induced itch sensation, referring to their application to drug development.

Prurigo nodularis (PN) is a chronic skin dermatosis with hyperkeratotic and intensely pruritic nodules. Managing PN-associated itch is difficult because its aetiology is still unknown. This study aimed to investigate the correlation between itch intensity in PN and the expression of a pruritogenic cytokine interleukin (IL)-31, its receptor complex components IL-31 receptor α (IL-31RA) and oncostatin M receptor β (OSMRβ), and oncostatin M (OSM), which is a ligand of OSMR β, through immunofluorescence staining examination. Itch intensity in PN was closely correlated with the number of dermal IL-31(+) cells (Spearman's r = 0.551, p 0.05), dermal IL-31RA(+) cells (r = 0.475, p 0.05) and dermal OSM(+) cells (r = 0.505, p 0.05). In addition, the number of dermal OSMRβ (+) cells was increased in PN (t test, p 0.05), despite not being correlated with itch intensity (Spearman's r = 0.375, p 0.05). Major cellular sources of dermal IL-31 were T cells (27.0% of total IL-31-expressing cells) and macrophages (35.0%), while those of OSM were mainly T cells (49.8%) and mast cells (26.8%). IL-31RA-expressing dermal cells were mostly mast cells (49.3%) and macrophages (36.6%), and OSMRβ was mainly expressed by macrophages (51.8%) in the dermis. These findings indicate that IL-31 (mainly from macrophages and T cells) and OSM (principally from T cells and mast cells) stimulate dermal cells expressing IL-31RA and OSMRβ (e.g. macrophages), which may further promote itch and inflammation in PN. This complex dermal milieu of cell/cytokine/receptor network can be a therapeutic target for PN-associated itch.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, has important roles in renal diseases. The relationship between OSM and kidney stone disease, however, remains unclear. To investigate the roles of OSM in the development of kidney stone disease, we generated a mouse model of renal crystal formation using OSM receptor β (OSMRβ)-deficient mice (OSMRβ−/− mice). There were fewer renal crystal deposits in OSMRβ−/− mice than in wild-type (WT) mice. Crystal-binding molecules (osteopontin, annexin A1, and annexin A2), inflammatory cytokines (TNF-α and IL-1β), and fibrosis markers (TGF-β, collagen 1a2, and α-smooth muscle actin) were also decreased in the kidneys of OSMRβ−/− mice compared with those in WT mice. Immunofluorescence staining showed that OSMRβ was expressed in renal tubular epithelial cells (RTECs) and renal fibroblasts in the model of renal crystal formation. In the cultured RTECs and renal fibroblasts, OSM directly induced the expression of crystal-binding molecules and fibrosis markers. Expressions of inflammatory cytokines were increased by stimulation with OSM in cultured renal fibroblasts. OSM may promote the formation of renal crystal deposits by directly acting on RTECs and renal fibroblasts to produce crystal-binding molecules and inflammatory cytokines.

An increased expression of oncogenic microRNA miR551b-3p (also known as miR551b) occurs in a subset of breast cancer due to genomic amplification of 3q26.2 locus. Using in silico and clinical sample analysis of breast cancer patient datasets, we identified that those breast cancer samples that encompass miR551b amplification express high levels of STAT3 mRNA and Oncostatin (OSM) family genes in triple-negative breast cancer (TNBC). Furthermore, high expression of Oncostatin family genes associates with poor outcome in estrogen receptor- negative breast cancer patients. In this study, we identified a previously unexplored mechanism that miR551b-3p promotes breast cancer progression and tumor growth by direct interaction of miR551b-3p with STAT3 promoter thereby activating STAT3 transcription. As a consequence, STAT3 upregulates a cytokine Oncostatin and its receptor Oncostatin M receptor (OSMR) and their interaction further induces STAT3 phosphorylation and an autocrine self-reinforcing loop in TNBC cells. In this study, we demonstrate that overexpression of miR551b-3p promoted proliferation, invasion and migration, epithelial to mesenchymal transition (EMT) and spheroid formation of breast cancer cells and its inhibition decreased the expression of miR551b-3p by inhibiting OSM, OSMR, IL6ST, IL31RA, phosphorylated and total STAT3 in breast cancer cells and reduced tumor cell growth. Overall, our results provide the first evidence that miR551b regulates OSM family gene expression by activating STAT3 and thereby promoting tumor cell growth and metastasis in breast cancer cells. Therefore, targeting miR-551b-3p-STAT3-OSMR axis and inhibiting their levels will provide an unprecedented therapeutic opportunity in breast cancer. Citation Format: Anjali Geethadevi, Deepak Parashar, Miriam Ragle Aure, Jasmine George, Changliang Chen, Jyotsna Mishra, Andliena Tahiri, Bindu Nair, Amadou Camara, Vessela N Kristensen, Sunila Pradeep, Pradeep Chaluvally Raghavan. miR551b-3p promotes Oncostatin M signaling in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-05-04.

Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR–IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR–IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling in vitro. Importantly, these antibody clones inhibited the growth of ovarian cancer cells in vitro and in vivo by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR–IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. Significance: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.

Background & Aims Gemcitabine resistance is rapidly acquired by pancreatic ductal adenocarcinoma (PDAC) patients. Novel approaches that predict the gemcitabine response of patients and enhance gemcitabine chemosensitivity are important to improve patient survival. We aimed to identify genes as novel biomarkers to predict the gemcitabine response and the therapeutic targets to attenuate chemoresistance in PDAC cells. Methods Genome-wide RNA interference screening was conducted to identify genes that regulated gemcitabine chemoresistance. A cell proliferation assay and a tumor formation assay were conducted to study the role of lethal giant larvae homolog 1 (LLGL1) in gemcitabine chemoresistance. Levels of LLGL1 and its regulating targets were measured by immunohistochemical staining in tumor tissues obtained from patients who received gemcitabine as a single therapeutic agent. A gene-expression microarray was conducted to identify the targets regulated by LLGL1. Results Silencing of LLGL1 markedly reduced the gemcitabine chemosensitivity in PDAC cells. Patients had significantly shorter survival (6 months) if they bore tumors expressing low LLGL1 level than tumors with high LLGL1 level (20 months) (hazard ratio, 0.1567; 95% CI, 0.05966–0.4117). Loss of LLGL1 promoted cytokine receptor oncostatin M receptor (OSMR) expression in PDAC cells that led to gemcitabine resistance, while knockdown of OSMR effectively rescued the chemoresistance phenotype. The LLGL1-OSMR regulatory pathway showed great clinical importance because low LLGL1 and high OSMR expressions were observed frequently in PDAC tissues. Silencing of LLGL1 induced phosphorylation of extracellular signal-regulated kinase 2 and specificity protein 1 (Sp1), promoted Sp1 (pThr453) binding at the OSMR promoter, and enhanced OSMR transcription. Conclusions LLGL1 possessed a tumor-suppressor role as an inhibitor of chemoresistance by regulating OSMR–extracellular signal-regulated kinase 2/Sp1 signaling. The data sets generated and analyzed during the current study are available in the Gene Expression Omnibus repository (ID: GSE64681)., Graphical abstract

Summary: Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the “oncostatin signaling module,” which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells. : Parashar et al. demonstrate that the mature microRNA-551b-3p translocates to the nucleus for transcriptional activation of STAT3 gene. As a consequence, miR551b activates an autocrine signaling loop through the upregulation of oncostatin family genes, including oncostatin, and its receptors for the growth and metastasis of triple-negative breast cancer. Keywords: miR551b, oncostatin, STAT3, OSMR, miRNA-therapy, IPO8, RNAi

Oncostatin M receptor (OSMR) is a member of the interleukin 6 (IL-6) receptor family that transduces signaling events of Oncostatin M (OSM). OSM–OSMR signaling plays a key role in inflammation and cancer progression. However, the role of OSM–OSMR in gastric cancer (GC) is still unknown. OSMR expression in GC was determined by real-time PCR (RT-PCR), immunohistochemistry (IHC) and Western blot. The effects of OSM–OSMR on GC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in vitro and metastasis in vivo were examined. The pathways underlying OSM–OSMR signaling were explored by Western blot. Regulatory mechanism between SP1 and OSMR was explored in vitro. OSMR was highly expressed in GC tissues and its expression level was closely associated with age, T stage, Lauren classification, lymph node metastasis, TNM stage and worse prognosis of patients with GC. Knockdown of OSMR expression in GC cells significantly inhibited cell proliferation, migration, invasion, and EMT in vitro, as well as tumorigenesis and peritoneal metastasis in vivo induced by OSM. These effects mediated by OSM–OSMR were dependent on the activation of STAT3/FAK/Src signaling. SP1 could bind to the promoter region of human OSMR gene from − 255 to − 246 bp, and transcriptionally regulated OSMR overexpression in GC cells. OSM–OSMR contributes to GC progression through activating STAT3/FAK/Src signaling, and OSMR is transcriptionally activated by SP1.

BACKGROUND:Triple negative breast cancer (TNBC) has poor prognosis, lack of targeted therapies and are often refractory to conventional chemotherapy treatments. Therefore, finding new therapeutic targets for those tumours is an unmet need with high clinical impact. In this context, Oncostatin M receptor (OSMR) is a promising therapeutic target as it is over-expressed in this tumour subtype and its activation promotes invasiveness (Guo L, et al. 2013 Oncogene; West NR, et al.2014 Oncogene). We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis (Caffarel MM, et al 2013 Journal of Pathology; Caffarel MM, et al 2014 Journal of Pathology; Kucia-Tran JA, et al. 2016 Brit J Cancer; Kucia-Tran JA, et al 2018 Journal of Pathology). We now investigate the role of OSMR in breast cancer progression. METHODS: To address this issue we use a wide array of tools including in vitro cell cultures and in vivo models. The expression of OSMR pathway was analysed in FFPE samples and large datasets of publicly available breast cancer samples (METABRIC, n=1462; and TCGA, n=547). RESULTS: OSMR and its ligand Oncostatin M (OSM) are over-expressed in basal tumours, where they associate with shorter overall survival (p=0.015). While OSMR is expressed by breast cancer cells and cancer associated fibroblasts, the main source of OSM seems to be primarily macrophages. OSM treatment of breast cancer cells induces the expression of important mediators of angiogenesis and invasion. Importantly, OSMR activation accelerates tumour onset, tumour growth and metastasis in orthotopic xenografts in nude mice. CONCLUSIONS: Our results support that OSMR pathway may have an important role in the initiation and progression of breast cancer and that it could be a promising candidate for therapeutic targeting in TNBC. OSMR could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer. Citation Format: Alvarez I, Araujo A, Abaurrea A, Rezola R, Urruticoechea A, Lawrie C, Caffarel MM. New targets in triple negative breast cancer: Role of Oncostatin M receptor pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-16.

BACKGROUND Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic skin disorder. The genetic basis of familial (f)PLCA involves mutations in the oncostatin M receptor (OSMR) and interleukin-31 receptor A (IL31RA) genes, but the disease pathophysiology is not fully understood. AIM To investigate the OSMR mutation spectrum in patients with sporadic (s)PLCA/fPLCA, lichen/macular PLCA in mainland China. METHODS This study was carried out on 64 patients with sPLCA, along with 36 with fPLCA and 10 unaffected individuals collected from 23 unrelated Chinese families. Genomic DNA was extracted from peripheral blood samples. Mutation screening of 17 OSMR exons was performed by Sanger sequencing. RESULTS PLCA lesions are typically localized to the shins, forearm and back. Sequence analysis of OSMR exons demonstrated that the OSMR missense mutation rate in patients with fPLCA (63.89%) was significantly higher than that in patients with sPLCA (34.38%). The male/female ratio of patients carrying a homozygous OSMR mutation (0.29) was significantly lower than that of patients carrying a heterozygous OSMR mutation (1.08; P

Background Oncostatin M receptor (OSMR) represents a part of the interleukin-six (IL6) cytokine group that was discovered recently to be closely associated with cell’s growth and differentiation, inflammation, and enhancement of metastatic capacity. A comprehensive study suggests a close relationship between OSMR and papillary thyroid cancer, colorectal cancer, breast cancer, and other tumors. However, the relationship between OSMR and bladder cancer has yet to be determined. Methods Three hundred six patients (including 142 patients with muscle-invasive bladder cancer and 164 patients with non-muscle-invasive bladder cancer) as well as 459 normal controls were included in this study. Two tag SNPs of OSMR, rs2278329, and rs2292016 were genotyped by TaqMan® SNP Genotyping Assay method and then the associations with bladder cancer were analyzed, as well as risk factors and prognosis. Results Patients with bladder cancer and controls did not differ significantly in terms of genotype frequencies and allele frequency distribution of rs2278329 (P = 0.77, OR = 0.97) and rs2292016 (P = 0.39, OR = 1.20) respectively. For rs2278329, no differences were found in terms of risk factors in stratified analyses. However, rs2292016 was associated with recurrence and tumor grade. GT/TT was found to increase the risk of relapse compared to the patients without allele T (GG genotype) (P = 0.016, OR = 1.878, 95% CI = 1.12–3.14) with the T allele of rs2292016 being a risk factor for recurrence (P = 0.032, OR = 0.67, 95% CI = 0.47–0.97). Besides, patients with GT genotype often present with high-grade bladder cancer (P = 0.003, OR = 2.33, 95% CI = 1.32–4.17). Multiple Cox regression analysis showed that rs2278329 and rs2292016 were related to the recurrence-free survival and overall survival in non muscle invasive bladder cancer (NMIBC) patients. For rs2278329, GA genotype could affect recurrence-free survival (P = 0.01, OR = 2.16, 95% CI = 1.17–3.98). For rs2292016, TT/GT genotype had a lower risk of death compared with GG homozygote genotype, and T was a protective factor for overall survival in bladder cancer (P = 0.029, OR = 0.22, 95% CI = 0.06–0.86). Conclusions OSMR genotype frequencies were found to be associated with higher recurrence in bladder cancer, and it may serve as a biomarker candidate gene to predict prognosis of this disease. Further validation of OSMR as biomarker is required.

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.

Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRβ) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRβ) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.

Interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), rhinitis and airway hyperreactivity. In AD, IL-31 has been identified as one of the main ‘drivers’ of its cardinal symptom pruritus. Here, we aim to summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-produced cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, and stimulating itch and neuronal outgrowth through activation of the heterodimer receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor β. IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well as various innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31 downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo nodularis. For example, whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.

Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression1,2. However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.

Interleukin-31 (IL-31) is a major protein involved in severe inflammatory skin disorders. Its signaling pathway is mediated through two type I cytokine receptors, IL-31RA (also known as the gp130-like receptor) and the oncostatin M receptor (OSMR). Understanding molecular details in these interactions would be helpful for developing antagonist anti-IL-31 monoclonal antibodies (mAbs) as potential therapies. Previous studies suggest that human IL-31 binds to IL-31RA and then recruits OSMR to form a ternary complex. In this model, OSMR cannot interact with IL-31 in the absence of IL-31RA. In this work, we show that feline IL-31 (fIL-31) binds independently with feline OSMR using surface plasmon resonance, an enzyme-linked immunosorbent assay, and yeast surface display. Moreover, competition experiments suggest that OSMR shares a partially overlapping epitope with IL-31RA. We then used deep mutational scanning to map the binding sites of both receptors on fIL-31. In agreement with previous studies of the human homologue, the binding site for IL31-RA contains fIL-31 positions E20 and K82, while the binding site for OSMR comprises the "PADNFERK" motif (P103-K110) and position G38. However, our results also revealed a new overlapping site, composed of positions R69, R72, P73, D76, D81, and E97, between both receptors that we called the "shared site". The conformational epitope of an anti-feline IL-31 mAb that inhibits both OSMR and IL-31RA also mapped to this shared site. Combined, our results show that fIL-31 binds IL-31RA and OSMR independently through a partially shared epitope. These results suggest reexamination of the putative canonical mechanisms for IL-31 signaling in higher animals.

Background: Acute intestinal ischemia-reperfusion injury (AIIRI) is a devastating clinical condition relevant to multiple diseases processes, including sepsis, trauma, transplantation, and burns. An AIIRI is a contributor to the development of multiple organ dysfunction syndrome (MODS). Oncostatin M (OSM)/oncostatin M receptor (OSMR) signaling is an unrecognized and novel candidate pathway for the mediation of MODS. In this study, we hypothesized that OSM mediates the injury mechanism of AIIRI leading to MODS. Methods: Wild-type (WT) and OSMR-knockout (OSMR-/-) C57BL/6 mice underwent AIIRI using a well-established model of selective occlusion of the superior mesenteric artery (SMA). Serum cytokine concentrations were measured using a multiplex detection system. Further tissue analysis was conducted with polymerase chain reaction, enzyme-linked immunosorbent assay, Western blots, and histologic review. Results: Survival was significantly higher in WT than in OSMR-/- groups at 30 minutes of ischemia with 2 hours of reperfusion (100% versus 42.9%; P = 0.015). No significant differences in the degree of local intestinal injury was seen in the two groups. In contrast, the degree of lung injury, as evidenced by myeloperixodase activity, was lower in OSMR-/- animals in the early AIIRI groups. There was a greater degree of renal dysfunction in OSMR-/- mice. Oncostatin M mediated interleukin (IL)-10 upregulation, with WT animals having significantly lower IL-10 concentrations (52.04 ± 23.06 pg/mL versus 324.37 ± 140.35 pg/mL; P = 0.046). Conclusion: Oncostatin M signalling is essential during acute intestinal ischemia-reperfusion injury. An OSMR deficiency results in decreased early lung injury but increased renal dysfunction. There was a significantly increased mortality rate after AIIRI in mice with OSMR deficiency. Augmentation of OSM may be a novel immunomodulatory strategy for AIIRI.

Background Although several studies have shown the role of interleukin-31 (IL-31) and its receptors in inducing pruritus in certain skin disorders, knowledge of its role in post-burn hypertrophic scars is insufficient. Therefore, the histopathological expression levels of IL-31, IL-31 receptor alpha (IL-31RA), and oncostatin M receptor (OSMR) in post-burn hypertrophic scar tissues were investigated and compared with normal tissue expression levels. Methods Samples of hypertrophic scar tissue were obtained from 20 burn patients through punch biopsy. Normal samples were obtained from areas adjacent to the burn injury site of the same patients. Samples were placed in 10% neutral buffered formalin, embedded in paraplast, and processed into serial 5-μm sections. Immunohistochemistry results were semi-quantitatively evaluated for IL-31, IL-31RA, and OSMR. By hematoxylin and eosin staining, epidermal and dermal thickness were assessed with a microscope and digital camera. Intensities were rated on a scale of 1 to 4. Results Percentages for IL-31, IL-31RA, and OSMR in the epidermal basal layer cell cytoplasm were significantly greater in the burn scar tissue compared to normal skin, as well as the dermal and epidermal thickness (p < .05). There was a significant difference in IL-31 epidermal basal layer intensity in burn scar tissue compared to normal skin (p < .05). Besides the OSMR basal layer intensity, IL-31 and IL-31RA intensities between the burn scar and normal tissues were not significant. However, correlations were significant, indicating that the greater the infiltration percentage, the higher the intensity (p < .05). Conclusions IL-31, IL-31RA, and OSMR expression levels are increased in hypertrophic scars compared with normal tissue.

Objective This study examined the phenotypic effects of adipocyte-specific oncostatin M receptor (OSMR) loss in chow-fed mice. Methods Chow-fed adipocyte-specific OSMR knockout (FKO) mice and littermate OSMRfl/fl controls were studied. Tissue weights, insulin sensitivity, adipokine production, and stromal cell immunophenotypes were assessed in epididymal fat (eWAT); serum adipokine production was also assessed. In vitro, adipocytes were treated with oncostatin M, and adipokine gene expression was assessed. Results Body weights, fasting blood glucose levels, and eWAT weights did not differ between genotypes. However, the eWAT of OSMRFKO mice was modestly less responsive to insulin stimulation than that of OSMRfl/fl mice. Notably, significant increases in adipokines, including C-reactive protein, lipocalin 2, intercellular adhesion molecule-1, and insulinlike growth factor binding protein 6, were observed in the eWAT of OSMRFKO mice. In addition, significant increases in fetuin A and intercellular adhesion molecule-1 were detected in OSMRFKO serum. Flow cytometry revealed a significant increase in leukocyte number and modest, but not statistically significant, increases in B cells and T cells in the eWAT of OSMRFKO mice. Conclusions The chow-fed OSMRFKO mice exhibited adipose tissue dysfunction and increased proinflammatory adipokine production. These results suggest that intact adipocyte oncostatin M-OSMR signaling is necessary for adipose tissue immune cell homeostasis.

IL-31 is a novel cytokine expressed in many human tissues and involved mainly in TH2-weighted inflammation. IL-31 signals through a receptor complex consisting of IL-31 receptor α and oncostatin M receptor β. The available data show that IL-31 is strongly linked with chronic pruritic skin disorders, such as atopic eczema, and represents a novel target for directed drug therapy. Regulation of immune responses and cellular differentiation and proliferation are recently elucidated effects of IL-31, suggesting a more complex and diverse area of effect for this novel cytokine. This review summarizes the current knowledge on IL-31 and its receptors and the involvement of IL-31 in diseases both in human subjects and mouse models.

The oncostatin M (OSM) receptor (OSMR) shows frequent gene copy number gains and overexpression in cervical squamous cell carcinomas (SCCs), associated with adverse clinical outcomes. In SCC cells that overexpress OSMR, the major ligand OSM induces multiple pro-malignant effects, including invasion, secretion of angiogenic factors, and metastasis. Here, we demonstrate, for the first time, that OSMR overexpression in SCC cells activates cell-autonomous feed-forward signalling, via further expression of OSMR and OSM and sustained STAT3 activation, despite expression of the negative regulator suppressor of cytokine signalling 3 (SOCS3). The pro-malignant effects associated with OSMR overexpression are critically mediated by JAK-STAT3 activation, which is induced by exogenous OSM and also by autocrine OSM-OSMR interactions. Importantly, specific inhibition of OSM-OSMR interactions by neutralizing antibodies significantly inhibits STAT3 activation and feed-forward signalling, leading to reduced invasion, angiogenesis, and metastasis. Our findings are supported by data from 1254 clinical SCC samples, in which OSMR levels correlated with multiple cognate genes, including OSM, STAT3, and downstream targets. These data strongly support the development of OSM-OSMR-blocking antibodies as biologically targeted therapies against SCCs of the cervix and other anatomical sites. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Deciphering the complex milieu that makes up the tumor microenvironment (TME) and the signaling engaged by TME cytokines continues to provide novel targets for therapeutic intervention. The IL-6 family member oncostatin M (OSM) has recently emerged as a potent driver of tumorigenesis, metastasis, and therapy failure, molecular programs most frequently attributed to IL-6 itself. In a recent issue of The Journal of Pathology, Kucia-Tran et al describe how elevated oncostatin M receptor (OSMR) expression results in a feed-forward loop involving the de novo production of both OSM and OSMR to facilitate aggressive properties in squamous cell carcinoma (SCC). Here, we discuss how new findings implicating OSM in conferring aggressive cancer cell properties can be leveraged to suppress metastatic outgrowth and therapy failure in SCC as well as other cancers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

SummaryLatent factor modelling applied to single-cell RNA-sequencing (scRNA-seq) data is a useful approach to discover gene signatures associated with cell states. However, it is often unclear what method is best suited for specific tasks and how latent factors should be interpreted from a biological perspective.Here, we compare four state-of-the-art methods and explore their stability, predictive power and coverage of known biology. We then propose an approach that leverages the derived latent factors to directly assign pathway activities to specific cell subsets. By applying this framework to scRNA-seq datasets from biopsies of rheumatoid arthritis and systemic lupus erythematosus patients, we discover both known and novel disease-relevant gene signatures in specific cellular subsets in a fully unsupervised way. Focusing on rheumatoid arthritis, we identify an inflammatory Oncostatin M receptor signalling signature active in a subset of synovial fibroblasts and dysregulation of the GAS6 - MERTK axis in a subset of synovial monocytes with efferocytic function.Overall, we provide insights into strengths and weaknesses of latent factors models for the analysis of scRNA-seq data, we develop a framework to identify cell subtypes in a function- or phenotype-driven way and use it to identify novel pathways dysregulated in rheumatoid arthritis.

Glioblastoma Multiform (GBM) is the most aggressive primary tumor in the adult brain. The present standard of care includes surgical removal of the tumors followed by treatment with Temozolomide (TMZ) and radiation therapy. Despite intense efforts and advances in surgery and combination therapy, the median survival rate for GB patients remain 16 months following diagnosis. EGFRvIII/STAT3 signaling plays critical roles in GBM pathogenesis. We have recently discovered that the tumorigenic capacity of EGFRvIll/STAT3 pathway crucially depends on the cytokine receptor for Oncostatin M (OSMR). OSMR is a required co-receptor of EGFRvIII and a direct transcriptional target of STAT3. Strikingly, OSMR is highly expressed in brain tumor stem cells (BTSCs), a population of self-renewing malignant stem cells within GBM that contribute to tumor growth, recurrence and therapeutic resistance. We have generated therapeutic monoclonal antibodies against OSMR (OSMR mAb) that function as powerful inhibitors of OSMR. Treatment of BTSCs with OSMR mAb resulted in inhibition of OSMR-mediated signaling pathways and significantly impaired the phosphorylation of STAT3. Strikingly, treatment of BTSCs with OSMR mAb significantly attenuated BTSC self-renewal in limiting dilution assay and sensitized their response to tyrosine kinase inhibitors (TKI), ionizing radiation and TMZ. Using patient derived stem cell tumor xenografts, we have shown that OSMR mAb significantly reduced tumor growth compared to IgG control. Together, our findings suggest that targeting OSMR using therapeutic monoclonal antibodies in combination with EGFR inhibitors and/ or the current standard of care may provide a promising therapeutic strategy for glioblastoma.

Neurogenic heterotopic ossifications (NHO) are very incapacitating complications of traumatic brain and spinal cord injuries (SCI) which manifest as abnormal formation of bone tissue in periarticular muscles. NHO are debilitating as they cause pain, partial or total joint ankylosis and vascular and nerve compression. NHO pathogenesis is unknown and the only effective treatment remains surgical resection, however once resected, NHO can re-occur. To further understand NHO pathogenesis, we developed the first animal model of NHO following SCI in genetically unmodified mice, which mimics most clinical features of NHO in patients. We have previously shown that the combination of (1) a central nervous system lesion (SCI) and (2) muscular damage (via an intramuscular injection of cardiotoxin) is required for NHO development. Furthermore, macrophages within the injured muscle play a critical role in driving NHO pathogenesis. More recently we demonstrated that macrophage-derived oncostatin M (OSM) is a key mediator of both human and mouse NHO. We now report that inflammatory monocytes infiltrate the injured muscles of SCI mice developing NHO at significantly higher levels compared to mice without SCI. Muscle infiltrating monocytes and neutrophils expressed OSM whereas mouse muscle satellite and interstitial cell expressed the OSM receptor (OSMR). In vitro recombinant mouse OSM induced tyrosine phosphorylation of the transcription factor STAT3, a downstream target of OSMR:gp130 signaling in muscle progenitor cells. As STAT3 is tyrosine phosphorylated by JAK1/2 tyrosine kinases downstream of OSMR:gp130, we demonstrated that the JAK1/2 tyrosine kinase inhibitor ruxolitinib blocked OSM driven STAT3 tyrosine phosphorylation in mouse muscle progenitor cells. We further demonstrated in vivo that STAT3 tyrosine phosphorylation was not only significantly higher but persisted for a longer duration in injured muscles of SCI mice developing NHO compared to mice with muscle injury without SCI. Finally, administration of ruxolitinib for 7 days post-surgery significantly reduced STAT3 phosphorylation in injured muscles in vivo as well as NHO volume at all analyzed time-points up to 3 weeks post-surgery. Our results identify the JAK/STAT3 signaling pathway as a potential therapeutic target to reduce NHO development following SCI.

Synovial sarcoma is a soft tissue malignancy of the muscle tissue which primarily affects adolescents. While it is a rare disease, little advancement has been made in the treatment of this cancer. With an overall survival rate of roughly 40%, the need for new treatments for synovial sarcoma is evident. Oncostatin M Receptor (OSMR) is a type I cytokine receptor and is overexpressed in metastatic synovial sarcoma. OSMR does not have high expression in normal tissues, making it an ideal target for cancer therapy. We hypothesize that by using an anti-OSMR monoclonal antibody conjugated to a radioactive Cu67 isotope, synovial sarcoma can be targeted at both primary and metastatic locations through systemic therapy. Copper 67 is a gamma radiation emitting isotope which is tissue damaging and able to induce cell death in cancer cells. By conjugating the chelating molecule p-SCN-Bn-NOTA to an anti-OSMR antibody, Cu67 was able to be captured to the antibody. Capture efficiency of Cu67 was measured through TLC and found to be 64 % efficient. Binding studies through Surface Plasmon Resonance (SPR) found that the conjugation did not interfere with the binding affinity of the antibody. This data suggests that targeting OSMR through radio-immune therapy is a viable treatment and indicates further testing in animal models. Citation Format: Sarah Luelling. Oncostatin M receptor as a therapeutic target of radio-immune therapy in metastatic synovial sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 529.

AIM Over 7 million traumatic brain injuries (TBI) are reported each year in the United States. However, treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood. Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection. However, the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear. METHODS The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop. LPS was administered 7 days prior to TBI. LPS administration reduced locomotion, which recovered completely by time of injury. RESULTS LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum, possibly by downregulating the oncostatin M receptor. These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury. LPS preconditioning successfully prevented neurodegeneration near the corpus callosum, as measured by fluorojade B. CONCLUSION Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.

The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor β chain (OSMRβ) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMRβ in metabolic disorders remains unclear. Here, we report on the central role of OSMRβ in the protection against obesity and deregulation of glucose and lipids. We observed significantly varied expression levels of OSMRβ in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMRβ displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMRβ. Mechanistically, we showed that OSMRβ phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the liver. More importantly, the liver-restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMRβ knockout mice, whereas OSMRβ overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMRβ-mediated beneficial effects. In conclusion, hepatic OSMRβ expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades.

The objective of the present study was to evaluate the serum levels of soluble oncostatin M (OSM), OSM receptor (sOSMR) and glycoprotein130 (sgp130) in patients with systemic sclerosis (SSc), and the possible associations and correlations with clinical parameters.Serum levels of OSM, sOSMR and sgp130 were evaluated by ELISA in eighty-four SSc patients and eighty-four healthy volunteers.SSc patients had significantly elevated levels of sOSMR and sgp130 when compared with healthy individuals (p0.0001 and p = 0.025, respectively). Diffuse cutaneous SSc and limited cutaneous SSc patients also presented higher levels of sOSMR when compared with healthy individuals (p = 0.003 and p = 0.0001, respectively). Patients with digital ulcers presented higher levels of sOSMR when compared to those without ulcers (p = 0.034). However, sOSMR levels were lower in patients with esophageal dysfunction than patients without this involvement (p = 0.038). OSM levels were undetectable in serum from SSc patients and healthy volunteers.Serum levels of sOSMR and sgp130 are elevated in patients with systemic sclerosis. In addition, associations were observed with important clinical manifestations, suggesting that sOSMR is a candidate biomarker of this disease. More studies are needed to clarify the functions of IL-6 family cytokines in systemic sclerosis.

Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL-6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations-counter (MCP-counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity-related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

Primary localized cutaneous amyloidosis is a group of rare conditions where amyloid deposition is limited to the skin without systemic manifestations. Most cases are sporadic; however, mutations in the oncostatin M receptor (OSMR) and interleukin-31 receptor A (IL31RA) genes can cause a familial form of the condition in up to 10% of cases. Here, we describe a family in which 8 female individuals are affected by either macular amyloidosis or amyloidosis cutis dyschromica. To the best of our knowledge, a sex-specific expression or the coexistence of 2 different phenotypes of primary localized cutaneous amyloidosis in 1 pedigree has not yet been reported.

The IL-6 family cytokine, oncostatin M (OSM), has several physiological roles, but its exact role in adipose tissue homeostasis is still unclear. We recently reported that high-fat diet-fed male mice with an adipocyte-specific deletion of the OSM-specific receptor (OSMR FKO mice) were insulin-resistant and had increased markers of inflammation in epididymal adipose tissue (eWAT). In the current study, we more closely examined eWAT stromal cell populations in high-fat fed OSMR FKO mice using flow cytometry. Results from flow cytometry studies revealed that, despite no differences in eWAT weights between genotypes, OSMR FKO mice had significantly fewer stromal cells per gram eWAT. Although there were fewer stromal cells overall, a significantly higher percentage of these cells were CD45+ leukocytes. Significant decreases in the numbers of adipose tissue macrophages (CD64+; CD11c+/-) and preadipocytes (CD45-; CD31-; Sca1+) were also observed in OSMR FKO eWAT. A cytokine array was performed on eWAT to assess differences in tissue cytokine profiles that may contribute to the alterations observed in stromal cell populations. Array results indicated a significant decrease in stromal cell-derived factor 1 (SDF1) protein expression in eWAT of OSMR FKO mice. Future studies will focus on the role of adipocyte OSM signaling as a regulator of adipose tissue SDF1 production and stromal cell homeostasis. Overall, our results suggest a homeostatic role for adipocyte OSM signaling in the maintenance of stromal cell populations in gonadal fat. Disclosure C.M. Elks: None.

Oncostatin M (OSM) and interleukin-31 (IL-31) are two cytokines belonging to the IL-6 family which share a common signaling receptor subunit, the OSM receptor beta (OSMRβ). Both of them are released by monocytes/macrophages, dendritic cells and T lymphocytes in inflammatory situations and upon binding to their respective receptor complexes they signal mainly via the JAK/STAT pathway. Besides sharing many biochemical properties, both display divergent physiological functions. This review summarizes aspects of cytokine transcription and biosynthesis, cytokine-receptor interactions, cross-species activities, signal transduction and physiology delineated from recent findings in genetic mouse models for both cytokines, OSM and IL-31.

Background T H 2 cell–released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown. Objective We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31–induced itch and neuroepidermal communication in patients with AD. Methods Ca 2+ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31–stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects. Results In human DRGs we confirmed expression and co-occurrence of oncostatin M receptor β subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1–responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N-ethylmaleimide–sensitive factor activating protein receptor–dependent BNP release. In Grhl3PAR2 /+ mice house dust mite–induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype. Conclusion For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the skin. IL-31 enhances BNP release and synthesis and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function might be a novel therapeutic strategy for AD and pruritic conditions.

Background Oncostatin M (OSM) is a pleiotropic cytokine, highly expressed in the RA joint that displays both agonistic and antagonistic effects depending on the inflammatory microenvironment. This study examines the effect of OSM on inflammation, the Notch-1 signalling pathway which plays a critical role in vascular development and angiogenesis and finally on TNFα-induced pro-inflammatory mechanisms in Rheumatoid Arthritis. Objectives To examine the effect of OSM on cytokine/chemokine production, angiogenesis and the Notch-1 signalling pathway in synovial fibroblasts and endothelial cells and whether OSM potentiates the effects of TNFα-induced pro-inflammatory effects. Methods Primary RA synovial fibroblasts (RASFC) isolated from RA synovial biopsies obtained at time of knee arthroscopy and human dermal microvascular endothelial cells (HMVEC) were grown to confluence. RASFC and HMVEC were cultured with OSM (10ngml) alone or in combination with increasing concentrations of TNFα (0.01–1ng/ml). IL-6, IL-8, RANTES, GROα and MCP-1 cytokines/chemokines were quantified in culture supernatants by ELISA. Functionally, angiogenesis and invasion were assessed by matrigel tube formation and Transwell invasions assays respectively, and VEGF in cell lysates quantified by Real-time PCR. Finally, Notch-1, its ligands Delta-like-ligand 4 (DLL-4) and Jagged-1 (Jag-1) and downstream transcriptional repressors – Hey-1 and Hey-2 were quantified by Real-time PCR. Results OSM alone significantly induced IL-6 and MCP-1 while inhibiting IL-8 and GROα in RASFC and HMVEC culture supernatants, compared to basal control. OSM alone induced RANTES expression in HMVEC with little effect observed for RASFC. OSM potentiated the effect of increasing concentrations of TNFα on IL-6 and MCP-1 secretion from RASFC and HMVEC. Conversely OSM significantly inhibited TNFα-induced IL-8 and GROα secretion from both RASFC and HMVEC. Interestingly, OSM significantly inhibited TNFa-induced RANTES expression in HMVEC yet conversely potentiated this effect in RASFC. At a functional level, OSM induced both RASFC and HMVEC invasion and induced network formation and VEGF expression in HMVEC. OSM significantly induced Notch-1 in RASFC and HMVEC in a time dependent manner, but interestingly differentially regulated the Notch-1 ligands, with induction of Jag-1 only observed in RASFC, and induction of DLL-4 only observed in HMVEC. Finally OSM differentially regulated Notch-1 downstream transcriptional repressors in HMVEC, significantly inducing Hey-2 while simultaneously inhibiting Hey-1. Conclusions OSM is a pleiotropic cytokine that displays divergent effects with both pro- and anti-inflammatory mechanisms within the inflamed joint, effects that appear to be dependent on cell type and the inflammatory microenvironment. Targeting OSM or downstream signalling pathways may lead to new potential therapeutic strategies or adjuvant therapies, particularly for those patients who have sub-optimal responses. Disclosure of Interest None declared

The interleukin (IL)-6/gp130 family of cytokines (e.g., IL-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM)) play important roles in the central nervous system (CNS) during neuroinflammation and neurodevelopment. However, little is known regarding the responses by astroglia and microglia to this family of cytokines. Here the expression of the IL-6/gp130 cytokine receptors and subsequent signal pathway activation was examined in murine astrocytes and microglia in vitro. Astrocytes had high levels of OSMR mRNA while lower levels of IL-6R, LIFR and IL-11R mRNAs were also present. In comparison, in microglia there was no detectable OSMR mRNA, higher levels of IL-6R mRNA and lower levels of the LIFR and IL-11R mRNAs. The OSMR protein was present in astrocytes but was undetectable in microglia. Conversely, the IL-6R protein was present in microglia but not detectable in astrocytes. In astrocytes but not microglia, phosphorylation of STAT1 and STAT3 occurred in response to OSM, whereas both microglia and astrocytes responded to hyper-IL-6 (IL-6 linked to the soluble IL-6 receptor). Finally, in both microglia and astrocytes, OSM failed to activate NFκB or induce iNOS and nitrite production. We conclude: (1) notable differences exist in the expression of receptors utilized by the IL-6/gp130 family of cytokines in astrocytes and microglia, and (2) the findings provide a molecular basis for the differential response to OSM by astrocytes versus microglia and demonstrate a fundamental means for achieving cellular specificity in the response of these glial cells to this cytokine.

Background & Aims Oncostatin M (OSM) is an inflammatory cytokine which interacts with a heterodimeric receptor formed by gp130 and either OSMRβ or LIFR. Here we have analysed OSM and its receptors in livers with chronic hepatitis C (CHC) and studied the factors that regulate this system. Methods OSM, OSM receptors and OSM-target molecules were studied by immunohistochemistry and/or qPCR analysis in livers from CHC patients and controls. We determined the production of OSM by CD40L-stimulated antigen presenting cells (APC) and its biological effects on HuH7 cells containing HCV replicon (HuH7 Core-3′). Results OSM was upregulated in livers with CHC and its production was mapped to CD11c+ cells. OSM levels correlated directly with inflammatory activity and CD40L expression. In vitro studies showed that OSM is released by APC upon interaction with activated CD4+ T cells in a CD40L-dependent manner. Culture of HuH7 Core-3′ cells with supernatant from CD40L-stimulated APC repressed HCV replication and induced IL-7 and IL-15Rα. These effects were dampened by antibodies blocking OSM or gp130 and by silencing OSMRβ. In CHC livers OSMRβ and LIFR were significantly downregulated and their values correlated with those of OSM-induced molecules. Experiments in HuH7 cells showed that impaired STAT3 signaling and exposure to TGFβ1, two findings in CHC, are factors involved in repressing OSMRβ and LIFR, respectively. Conclusions OSM is a cytokine possessing vigorous antiviral and immunostimulatory properties which is released by APC upon interaction with CD40L present on activated CD4+ T cells. In livers with CHC, OSM is overexpressed but its biological activity appears to be hampered because of downregulation of its receptor subunits.

Cervical carcinoma is the second most common cause of cancer deaths in women worldwide. Treatments have not changed for decades and survival rates for advanced disease remain low. An exciting new molecular target for the treatment of cervical squamous cell carcinoma (SCC), and possibly for SCCs at other anatomical sites, is the oncostatin M receptor (OSMR). This cell surface cytokine receptor is commonly copy number gained and overexpressed in advanced cervical SCC, changes that are associated with significantly worse clinical outcomes. OSMR overexpression in cervical SCC cells results in enhanced responsiveness to the major ligand oncostatin M (OSM), which induces several pro-malignant effects, including a pro-angiogenic phenotype and increased cell migration and invasiveness. OSMR is a strong candidate for antibody-mediated inhibition, a strategy that has had a major impact on haematological malignancies and various solid tumours such as HER2-positive breast cancers. © 2013 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions, including inflammatory responses. However, the roles of OSM in metabolic diseases are unknown. We herein analyzed the metabolic parameters of OSM receptor β subunit-deficient (OSMRβ(-/-)) mice under normal diet conditions. At 32 weeks of age, OSMRβ(-/-) mice exhibited mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRβ(-/-) mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRβ(-/-) mice. Both OSM and OSMRβ were expressed strongly in the adipose tissue and little in some other metabolic organs, including the liver and skeletal muscle. In addition, OSMRβ is mainly expressed in the adipose tissue macrophages (ATMs) but not in adipocytes. In OSMRβ(-/-) mice, the ATMs were polarized to M1 phenotypes with the augmentation of adipose tissue inflammation. Treatment of OSMRβ(-/-) mice with an anti-inflammatory agent, sodium salicylate, improved insulin resistance. In addition, the stimulation of a macrophage cell line, RAW264.7, and peritoneal exudate macrophages with OSM resulted in the increased expression of M2 markers, IL-10, arginase-1, and CD206. Furthermore, treatment of C57BL/6J mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the development of insulin resistance at least in part through the polarization of the macrophage phenotypes to M2, and OSMRβ(-/-) mice provide a unique mouse model of metabolic diseases.

The somatic sensory neurons in dorsal root ganglia (DRG) detect and transmit a diverse array of sensory modalities, such as pain, itch, cold, warm, touch, and others. Recent genetic and single-cell RNA sequencing studies have revealed a group of DRG neurons that could be particularly relevant for acute and chronic itch information transmission. They express the natriuretic peptide type B (NPPB), as well as a cohort of receptors and neuropeptides that have been implicated in chronic itch manifestation, including the interleukin-31 receptor A (IL-31ra) and its coreceptor oncostatin M receptor (Osmr), the cysteinyl leukotriene receptor 2 (Cysltr2), somatostatin, and neurotensin. However, how these neurons are generated during development remains unclear. Here we report that Runx1 is required to establish all these molecular features of NPPB+neurons. We further show that while early embryonic Runx1 activity is required for the formation of NPPB+cells, at later stages Runx1 switches to a genetic repressor and thus its downregulation becomes a prerequisite for the proper development of these pruriceptors. This mode by Runx1 is analogous to that in controlling another group of pruriceptors that specifically express the chloroquine receptor MrgprA3. Finally, behavioral studies using both sexes of mice revealed marked deficits in processing acute and chronic itch inRunx1conditional knock-out mice, possibly attributable to impaired development of various pruriceptors.SIGNIFICANCE STATEMENTOur studies reveal a generalized control mode by Runx1 for pruriceptor development and consolidate a hierarchical control mechanism for the formation of sensory neurons transmitting distinct modalities. Among dorsal root ganglion neurons that initially express the neurotrophin receptor TrkA, Runx1 is necessary for the proper development of those neurons that innervate tissues derived from the ectoderm such as skin epidermis and hair follicles. These Runx1-dependent cutaneous sensory neurons are then divided into two groups based on persistent or transient Runx1 expression. The Runx1-persistent group is involved in transmitting mechanical and thermal information, whereas the Runx1-transient group transmits pruriceptive information. Such hierarchical control mechanisms may provide a developmental solution for the formation of sensory circuits that transmit distinct modalities.

Interleukin (IL)-31 is important for innate immunity in mucosal tissues and skin, and increased IL-31 expression participates in the pathogenesis of chronic inflammatory diseases affecting the skin, airways, lungs, and intestines. We investigated the contribution of mast cells to the induction of IL-31 production following infection with the periodontal pathogen, Porphyromonas gingivalis. We found that oral infection with P. gingivalis increased IL-31 expression in the gingival tissues of wild-type mice but not in those of mast cell-deficient mice. The P. gingivalis-induced IL-31 production by human mast cells occurred through the activation of the JNK and NF-κB signalling pathways and was dependent on the P. gingivalis lysine-specific protease gingipain-K. P. gingivalis infection induced IL-31 receptor α and oncostatin M receptor β expression in human gingival epithelial cells. Notably, the P. gingivalis-induced IL-31 production by mast cells led to the downregulation of claudin-1, a tight junction molecule, in gingival epithelial cells, resulting in an IL-31-dependent increase in the paracellular permeability of the gingival epithelial barrier. These findings suggest that IL-31 produced by mast cells in response to P. gingivalis infection causes gingival epithelial barrier dysfunction, which may contribute to the chronic inflammation observed in periodontitis.

Oncostatin M (OSM) is a secreted cytokine mainly involved in chronic inflammatory and cardiovascular diseases through binding to OSM receptor β (OSMR-β). Recent studies demonstrated that the presence of OSM contributed to the destabilization of atherosclerotic plaque. To investigate whether OSMR-β deficiency affects atherosclerosis, male OSMR-β−/−ApoE−/− mice were generated and utilized. Here we observed that OSMR-β expression was remarkably upregulated in both human and mouse atherosclerotic lesions, which were mainly located in macrophages. We found that OSMR-β deficiency significantly ameliorated atherosclerotic burden in aorta and aortic root relative to ApoE-deficient littermates and enhanced the stability of atherosclerotic plaques by increasing collagen and smooth muscle cell content, while decreasing macrophage infiltration and lipid accumulation. Moreover, bone marrow transplantation of OSMR-β−/− hematopoietic cells to atherosclerosis-prone mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT)3 in vivo and under Ox-LDL stimulation in vitro. Our findings suggest that OSMR-β deficiency in macrophages improved high-fat diet-induced atherogenesis and plaque vulnerability. Mech­anistically, the protective effect of OSMR-β deficiency on atherosclerosis may be partially attributed to the inhibition of the JAK2/STAT3 activation in macrophages, whereas OSM stimulation can activate the signaling pathway.

Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3–IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Muller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases.

IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31Rα and oncostatin M receptor β. Although several studies have aimed to investigate IL-31–mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin inflammation. Because dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c+ as well as monocyte-derived dendritic cells significantly upregulate the IL-31Rα receptor chain upon stimulation with IFN-γ. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-γ–dependent IL-31Rα expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of proinflammatory mediators, including TNF-α, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because these cytokines are crucially involved in skin inflammation, we hypothesize that IL-31–specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases.