Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes

The characteristics of human resistin (RETN) are unclear and controversial despite intensive adipose-focused research. Its transcriptional and functional similarity with the murine myeloid-specific and CCAAT/enhancer binding protein epsilon (Cebpe)-dependent gene, resistin-like gamma (Retnlg), is unexplored. We examined the human CEBPE-regulatory pathway by unbiased reference and custom gene expression assays. Real-time RT-PCR analysis demonstrated lack of both the transcriptional factor CEBPE and RETN expression in adipose and muscle cells. In contrast, primary myelocytic samples revealed a concerted CEBPE-RETN transcription that was significantly elevated in inflammatory synoviocytes relative to intact peripheral blood mononuclear cells (PBMC). Mouse Cebpe and Retnlg were predictably expressed in macrophages, whereas Retn was abundant in adipocytes. Quite the opposite, a low and inconsistent RETN transcription was seen in some human white adipose tissue (WAT) biopsies without any relationship to body mass index, insulin sensitivity, or fat depot. However, in these cases, RETN was co-detected with CEBPE and the leukocyte-specific marker, EMR1, indicating the presence of inflammatory cells and their possible resistin-mediated effect on adipocytes. Indeed, addition of human resistin to WAT in culture induced, like in PBMC, the inflammatory cytokines IL6, IL8 and TNF. Importantly, the expression of the adipose-specific markers CEBPA, FABP4 and SLC2A4 was unchanged, while the expected inhibitory effect was seen with TNF. Both cytokines increased the mRNA level of CCL2 and MMP3, which may further promote inflammation in WAT. Thus, the myeloid-restricted nature of CEBPE precludes the expression of RETN in human adipocytes which, however, are targeted by this innate immune-derived proinflammatory cytokine

Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients

Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome (MS). Psoriasis patients have a high prevalence of the MS. In this study, we investigated the statistics of circulating Th17-related cytokines and adipokines in psoriasis patients. Our study identified the significant elevation of serum IL-6, IL-21, IL-22, and resistin levels in psoriasis patients. Increased serum levels of IL-22 and adiponectin were positively correlated with Psoriasis Area and Severity Index (PASI). In contrast, serum high molecular weight adiponectin levels were decreased in psoriasis and negatively correlated with PASI

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Hypoxia-Induced Mitogenic Factor (HIMF/FIZZ1/RELMα) Recruits Bone Marrow-Derived Cells to the Murine Pulmonary Vasculature

. and localized to the media layer of the vessels. This finding suggests that these cells are of mesenchymal origin and differentiate toward myofibroblast and vascular smooth muscle. Structural location in the media of small vessels suggests a functional role in the lung vasculature. To examine a potential mechanism for HIMF-dependent recruitment of mesenchymal stem cells to the pulmonary vasculature, we performed a cell migration assay using cultured human mesenchymal stem cells (HMSCs). The addition of recombinant HIMF induced migration of HMSCs in a phosphoinosotide-3-kinase-dependent manner.These results demonstrate HIMF-dependent recruitment of BMD mesenchymal-like cells to the remodeling pulmonary vasculature

Prominent Bone Loss Mediated by RANKL and IL-17 Produced by CD4+ T Cells in TallyHo/JngJ Mice

Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis

The absence of MyD88 has no effect on the induction of alternatively activated macrophage during Fasciola hepatica infection

<p>Abstract</p> <p>Background</p> <p>Alternatively activated macrophages (AAMϕ) play important roles in allergies and responses to parasitic infections. However, whether signaling through toll-like receptors (TLRs) plays any role in AAMϕ induction when young <it>Fasciola hepatica </it>penetrates the liver capsule and migrates through the liver tissue is still unclear.</p> <p>Results</p> <p>The data show that the lack of myeloid differentiation factor 88 (MyD88) has no effect on the AAMϕ derived from the bone marrow (BMMϕ) <it>in vitro </it>and does not impair the mRNA expression of arginase-1, resistin-like molecule (RELMα), and Ym1 in BMMϕs. The Th2 cytokine production bias in splenocytes was not significantly altered in <it>F. hepatica</it>-infected mice in the absence of MyD88 <it>in vitro </it>and in the pleural cavity lavage <it>in vivo</it>. In addition, MyD88-deficiency has no effect on the arginase production of the <it>F. hepatica </it>elicited macrophages (Fe Mϕs), production of RELMα and Ym1 proteins and mRNA expression of Ym1 and RELMα of macrophages in the peritoneal cavity 6 weeks post <it>F. hepatica </it>infection.</p> <p>Conclusions</p> <p>The absence of MyD88 has no effect on presence of AAMϕ 6 weeks post <it>F. hepatica </it>infection.</p

Mosaic Convergence of Rodent Dentitions

BACKGROUND:Understanding mechanisms responsible for changes in tooth morphology in the course of evolution is an area of investigation common to both paleontology and developmental biology. Detailed analyses of molar tooth crown shape have shown frequent homoplasia in mammalian evolution, which requires accurate investigation of the evolutionary pathways provided by the fossil record. The necessity of preservation of an effective occlusion has been hypothesized to functionally constrain crown morphological changes and to also facilitate convergent evolution. The Muroidea superfamily constitutes a relevant model for the study of molar crown diversification because it encompasses one third of the extant mammalian biodiversity. METHODOLOGY/PRINCIPAL FINDINGS:Combined microwear and 3D-topographic analyses performed on fossil and extant muroid molars allow for a first quantification of the relationships between changes in crown morphology and functionality of occlusion. Based on an abundant fossil record and on a well resolved phylogeny, our results show that the most derived functional condition associates longitudinal chewing and non interlocking of cusps. This condition has been reached at least 7 times within muroids via two main types of evolutionary pathways each respecting functional continuity. In the first type, the flattening of tooth crown which induces the removal of cusp interlocking occurs before the rotation of the chewing movement. In the second type however, flattening is subsequent to rotation of the chewing movement which can be associated with certain changes in cusp morphology. CONCLUSION/SIGNIFICANCE:The reverse orders of the changes involved in these different pathways reveal a mosaic evolution of mammalian dentition in which direction of chewing and crown shape seem to be partly decoupled. Either can change in respect to strong functional constraints affecting occlusion which thereby limit the number of the possible pathways. Because convergent pathways imply distinct ontogenetic trajectories, new Evo/Devo comparative studies on cusp morphogenesis are necessary