Immune regulation of bone loss by Th17 cells

A significant macrophage and T-cell infiltrate commonly occurs in inflammatory joint conditions such as rheumatoid arthritis that have significant bone destruction. Cytokines produced by activated macrophages and T cells are implicated in arthritis pathogenesis and are involved in osteoclast-mediated bone resorption. The scope of the present review is to analyze current knowledge and to provide a better understanding of how macrophage-derived factors promote the differentiation of a novel T-helper subset (Th17) that promotes osteoclast formation and activation

γδTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis.

γδ T cells have been implicated in inflammatory diseases as an important link between the innate and adaptive immune responses, however, their role in inflammatory arthritis remain unclear. To define the contribution of γδ T cells in the pathogenesis of inflammatory arthritis, we performed gene transfer of IL-23 in B10.RIII mice to establish joint inflammation in the presence or absence of γδ T cells. We demonstrated that γδ T cell blockade has a protective effect on arthritis incidence and severity by preventing neutrophil accumulation in the blood, spleen and bone marrow as well as by reducing neutrophil infiltration into the joints. Furthermore, our data demonstrate that absence of γδ T cells was associated with an increase of IL-27 levels produced by neutrophils and dendritic cells, and systemic IL-27 expression also prevents IL-23-induced inflammatory arthritis and limits neutrophil expansion. Collectively our findings reveal an immunomodulatory effect of γδ T cells on neutrophils associated with IL-27 synthesis and secretion and indicate a novel link between IL-27 and the modulation of γδ T cells and neutrophils that can be targeted in the treatment of inflammatory arthritis

Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors.

IntroductionThe interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.MethodsHuman CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.ResultsIL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.ConclusionsCollectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases

The critical role of toll-like receptors - From microbial recognition to autoimmunity: A comprehensive review

Toll-like receptors (TLRs) constitute an important mechanism in the activation of innate immune cells including monocytes, macrophages and dendritic cells. Macrophage activation by TLRs is pivotal in the initiation of the rapid expression of pro-inflammatory cytokines TNF, IL-1β and IL-6 while promoting Th17 responses, all of which play critical roles in autoimmunity. Surprisingly, in inflammatory arthritis, activation of specific TLRs can not only induce but also inhibit cellular processes associated with bone destruction. The intercellular and intracellular orchestration of signals from different TLRs, their endogenous or microbial ligands and accessory molecules determine the activating or inhibitory responses. Herein, we review the TLR-mediated activation of innate immune cells in their activation and differentiation to osteoclasts and the capacity of these signals to contribute to bone destruction in arthritis. Detailed understanding of the opposing mechanisms of TLRs in the induction and suppression of cellular processes in arthritis may pave the way to develop novel therapies to treat autoimmunity.Instituto de Investigaciones Bioquímicas de La Plat

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs

Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis.

DNAX adaptor protein 12 (DAP12) is a trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells. Absence of functional Dap12 results in osteoclast defects and bone abnormalities. Because DAP12 has no extracelluar binding domains, it must pair with cell surface receptors for signal transduction. There are at least 15 known DAP12-associating cell surface receptors with distinct temporal and cell type-specific expression patterns. Our aim was to determine which receptors may be important in DAP12-associated bone pathologies. Here, we identify myeloid DAP12-associating lectin (MDL)-1 receptor (also known as CLEC5A) as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation. Activation of MDL-1 leads to enhanced recruitment of inflammatory macrophages and neutrophils to the joint and promotes bone erosion. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the clinical signs of autoimmune joint inflammation. These findings suggest that MDL-1 receptor may be a therapeutic target for treatment of immune-mediated skeletal disorders

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations