Galectin-3: an open-ended story.

The function of deciphering the biological information encoded by the glycome, which is the entire repertoire of complex sugar structures expressed by cells and tissues, is assigned in part to endogenous glycan-binding proteins or lectins. Galectins, a family of animal lectins that bind N-acetyllactosamine-containing glycans, have many roles in diverse immune cell processes, including those relevant to pathogen recognition, shaping the course of adaptive immune responses and fine-tuning the inflammatory response. How do galectins translate glycan-encoded information into tolerogenic or inflammatory cell programmes? An improved understanding of the mechanisms underlying these functions will provide further opportunities for developing new therapies based on the immunoregulatory properties of this multifaceted protein family.

Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation.

Inflammation is a critical process for eliminating pathogens, but can lead to serious deleterious effects if left unchecked Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology Galectins, a family of endogenous lectins with affinity for beta-galactoside-containing oligosaccharides, are expressed by several cells of the immune system and tissue-resident stromal cells According to their architecture, this family of glycan-binding proteins is classified in those containing one-carbohydrate-recognition domain (CRD) (proto-type), those containing two-CRD joined by a linker non-lectin domain (tandem-repeat) and those that have one-CRD attached to an N-terminal peptide (chimera-type) Accumulating evidence indicates that galectins play critical regulatory roles in immune cell response and homeostasis In this review, we summarize recent developments in our understanding of the galectins' roles within different immune cell compartments, and in the broader context of the inflammatory microenvironments In particular we illustrate the immunoregulatory role of three representative members of each galectin subfamily: galectin-1, -3 and -9 This body of knowledge, documenting the coming of age of galectins as potential immunosuppressive agents or targets for anti-inflammatory drugs, represents a sound basis to further explore their potential as novel therapies for autoimmune diseases, chronic inflammation and cancer

An Emerging Role for Galectins in Tuning the Immune Response: Lessons from Experimental Models of Inflammatory Disease, Autoimmunity and Cancer

For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis. During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts (RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential is underway.

/pdf/cells-of-the-synovium-in-rheumatoid-arthritis-synovial-omdha8gwfx.pdf

Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts

Galectin-3 (Gal-3) regulates basic cellular functions such as cell–cell and cell–matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed.

https://www.mdpi.com/1422-0067/19/2/379/pdf

Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z.

Objective

To characterize the expression pattern and role of galectin 3 and galectin 3 binding protein (G3BP) in rheumatoid arthritis (RA), in comparison with galectin 1, and to explore whether soluble galectin 3 and G3BP, investigated in serum, synovial fluid, or cell culture supernatant, are associated with disease.



Methods

Synovial tissues from patients with RA or osteoarthritis (OA), as well as from healthy controls, were analyzed for galectins 1 and 3 and G3BP by in situ hybridization and immunohistochemistry. Levels of galectin 3 and G3BP in serum and synovial fluid from patients with RA and OA and controls, as well as in cell culture supernatants, were determined by enzyme-linked immunosorbent assay (ELISA). In vitro, the intracellular expression of galectin 3 in RA and OA synovial fibroblasts after modulation with tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and anti-CD40 monoclonal antibodies was measured by flow cytometry.



Results

In RA, galectin 3 messenger RNA and protein stained throughout the synovial membrane, whereas G3BP was particularly expressed at sites of bone destruction. In contrast, the expression of galectin 1 was not uniform in different RA specimens, and was never found at sites of invasion. In OA and normal synovial tissues, only a small number of cells were positive for galectins and/or G3BP. Galectin 3 was elevated in RA sera and synovial fluids, whereas G3BP was increased in RA synovial fluids only. In RA, serum galectin 3 correlated with C-reactive protein levels, whereas G3BP was associated with joint destruction and/or synovial cell activation as measured by the levels of cartilage oligomeric matrix protein. In vitro, RA synovial fibroblasts showed an increased release of galectin 3 into culture medium, as measured by ELISA, but decreased secretion of G3BP. In RA synovial fibroblasts with low basal expression of galectin 3, TNFα increased its intracellular level in a dose-dependent manner. In contrast, IL-1β or anti-CD40 monoclonal antibodies showed no effect.



Conclusion

Our data indicate that galectin 3 and G3BP are not only involved in inflammation, but also contribute to the activation of synovial fibroblasts. The intracellular accumulation of galectin 3 can be enhanced by TNFα. Thus, galectin 3 and G3BP represent novel markers of disease activity in RA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.11287

Galectin 3 and its binding protein in rheumatoid arthritis

Absence of inducible retroviruses from synovial fibroblasts and synovial fluid cells of patients with rheumatoid arthritis.

Galectin-3 (Gal-3) is one of the soluble lectins that has key functions in inflammation, chemotaxis, cell adhesion and apoptosis. We examined the role of Gal-3 and Gal-3 binding protein (Gal-3BP) in rheumatoid arthritis (RA). Localization of Gal-3 and Gal-3BP in rheumatoid synovium was examined by immunohistochemistry and in situ hybridisation. Gal-3 and Gal-3BP concentrations in plasma and synovial fluid were measured by ELISA. Gal-3 protein and mRNA stained throughout the synovial membrane, and Gal-3BP expressed at the site of erosion in RA. Lower and scattered expression of both Gal-3 and Gal-3BP were detected in osteoarthritis synovium and normal synovium. ELISA revealed a marked increase of Gal-3 and Gal-3BP in synovial fluid of patients with RA compared with osteoarthritis patients and normal controls. Furthermore, the level of Gal-3 in serum correlated with the level of C-reactive protein in RA. In vitro, Gal-3 can induce the production of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-9 in synovial fibroblasts in a dose-dependent manner. Our data indicate that Gal-3 and Gal-3BP represent novel markers of disease activity in RA. Moreover, Gal-3 might contribute to the destruction of bone/cartilage in RA by the induction of MMPs.

/pdf/galectin-3-and-galectin-3-binding-protein-in-rheumatoid-5e387he3i6.pdf

Shiro Ohshima

Papers

Galectin 3 and its binding protein in rheumatoid arthritis

Absence of inducible retroviruses from synovial fibroblasts and synovial fluid cells of patients with rheumatoid arthritis.

Galectin-3 and galectin-3 binding protein in rheumatoid arthritis.