E74-like factor 3 (ELF3) is a transcription factor regulated by inflammation in different physio-pathological situations. Lipocalin-2 (LCN2) emerged as a relevant adipokine involved in the regulation of inflammation. In this study we showed for the first time the involvement of ELF3 in the control of LCN2 expression and its cooperation with nuclear factor-κB (NFκB). Our results will help to better understand of the role of ELF3, NFκB and LCN2 in the pathophysiology of articular cartilage.

Progranulin (PGRN) is a recently identified adipokine that is supposed to have anti-inflammatory actions. The proinflammatory cytokine interleukin-1β (IL1β) stimulates several mediators of cartilage degradation. Toll like receptor-4 (TLR4) can bind to various damage-associated molecular patterns, leading to inflammatory condition. So far, no data exist of PGRN effects in inflammatory conditions induced by IL1β or lipopolysaccharide (LPS). Here, we investigated the anti-inflammatory potential of PGRN in IL1β- or LPS-induced inflammatory responses of chondrocytes. Human osteoarthritic chondrocytes and ATDC-5 cells were treated with PGRN in presence or not of IL1β or LPS. First, we showed that recombinant PGRN had no effects on cell viability. We present evidence that PGRN expression was increased during the differentiation of ATDC-5 cell line. Moreover, PGRN mRNA and protein expression is increased in cartilage, synovial and infrapatellar fat pad tissue samples from OA patients. PGRN mRNA levels are upregulated under TNFα and IL1β stimulation. Our data showed that PGRN is able to significantly counteract the IL1β-induced expression of NOS2, COX2, MMP13 and VCAM-1. LPS-induced expression of NOS2 is also decreased by PGRN. These effects are mediated, at least in part, through TNFR1. Taken together, our results suggest that PGRN has a clear anti-inflammatory function.

Osteoarthritis (OA) and rheumatoid arthritis (RA), the most common rheumatic diseases, are characterized by irreversible degeneration of the joint tissues. There are several factors involved in the pathogenesis of these diseases including pro-inflammatory cytokines, adipokines and adhesion molecules.

Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here, we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells and found 168 phosphorylations regulated upon IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ17 cells. IL-23-induced RLC phosphorylation required Janus kinase 2 (JAK2) and Rho-associated protein kinase (ROCK) catalytic activity, and further study of the IL-23/ROCK connection revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells through ROCK activation. In addition, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work (i) provides new insights into phosphorylation networks that control Th17 cells, (ii) widely expands the current knowledge on IL-23 signaling, and (iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.

Progranulin (PGRN) is a glycoprotein formed by 593 amino acids encoded by the GRN gene. It has an important role in immunity and inflammatory response, as well as in tissue recovery. Its role in musculoskeletal inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and intervertebral disc degeneration disease (IVDD), is, nowadays, an important target to investigate. The objective of this review is to systematically sum up all the recent findings concerning PGRN as a target in the development and resolution of the inflammatory diseases. PubMed was examined with the terms combinations (Progranulin) AND (Lupus Erythematosus, Systemic), (Progranulin) AND (Arthritis, Rheumatoid), and (Progranulin) AND (Intervertebral Disc Degeneration). PubMed was examined with the terms combinations (Atsttrin) AND (Lupus Erythematosus, Systemic), (Atsttrin) AND (Arthritis, Rheumatoid), and (Atsttrin) AND (Intervertebral Disc Degeneration). Moreover, research through Web of Science was performed searching the same items. The inclusion criteria were: studies whose main topic were progranulin, or atsttrin, with emphasis on the three selected diseases. On the other hand, the exclusion criteria were studies that only focused on diseases not related to RA, lupus or IVDD, in addition to the previous published literature reviews. Since few results were obtained, we did not filter by year. The records assessed for eligibility were 23, including all the studies with the information in state of art of progranulin and its capability to be a potential target or treatment for each one of the selected diseases. As these results are descriptive and not clinical trials, we did not perform risk of bias methods. Within these results, many studies have shown an anti-inflammatory activity of PGRN in RA. PGRN levels in serum and synovial fluids in RA patients were reported higher than controls. On the other hand, serum levels were directly correlated with SLE disease activity index, suggesting an important role of PGRN as a player in the progression of inflammatory diseases and a therapeutical approach for the recovery. This review has some limitations due to the small number of studies in this regard; therefore, we highlight the importance and the necessity of further investigation. No external funding was implicated in this systematical review.

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1β, MIP1α, MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.