Research Topic

Proteoglycans and Glycosaminoglycan Modification in Immune Regulation and Inflammation

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Proteoglycans are a ubiquitous family of heavily glycosylated molecules consisting of a core protein with one or multiple covalently-attached linear anionic glycosaminoglycan (GAG) chains. The composition of GAGs is highly diverse and depends on the coherency and expression of numerous factors, including ...

Proteoglycans are a ubiquitous family of heavily glycosylated molecules consisting of a core protein with one or multiple covalently-attached linear anionic glycosaminoglycan (GAG) chains. The composition of GAGs is highly diverse and depends on the coherency and expression of numerous factors, including multiple GAG-modifying enzymes. Importantly, the composition and functional properties of GAGs are regulated in a spatiotemporal and cell type-specific fashion. Precise GAG modifications drive interactions with immune cells, pathogens, and specific protein ligands as exemplified by the heparan sulfate (HS) binding motif for antithrombin III, FGF2, PDGF and others. However, it is still unclear which cues and intracellular factors, including epigenetics, control the transcription and translation of GAG biosynthetic machinery and proteoglycan core proteins. Moreover, only recently have researchers started to search for transcriptional regulators. A critical question in the field is thus how cells dynamically regulate and coordinate proteoglycan structure.

The immune system is equally complex. First, a large repertoire of different immune cells needs to be replenished at a vast and constant rate; secondly, immune cells continuously traffic through the body in search of infectious agents and tissue damage; thirdly, innate and adaptive immune responses are initiated locally and in the draining lymphoid organs; and finally, immune processes need to be regulated to safeguard against development of autoimmunity. While this is a simplified overview, it underscores the complexity of immune responses. Most importantly, each individual process is critically orchestrated by a plethora of specific cytokines and chemokines to ensure protective immunity, without development of autoimmunity. Nearly all these soluble factors have demonstrable GAG-binding properties and require GAG interaction for their bioactivity, leading to an increasing appreciation that proteoglycans and GAGs play important roles in immune regulation and inflammation. Therefore, it is of great importance to better understand the regulatory pathways that control the functional outcome of GAG biosynthesis and degradation. Rapid local environmental changes are required upon induction of immune responses, and several studies demonstrate that disruption of specific GAG modifications has detrimental consequences on lymphocyte development, immune cell migration, or adaptive immunity. However, our understanding of the exact regulatory mechanisms and signaling pathways that control these modifications is incomplete.

The main goal of this Research Topic is to provide better understanding of the specific mechanisms (epigenetic, transcriptional and translational) that regulate proteoglycan and GAG biosynthesis in the immune system, and to establish how proteoglycans control diverse aspects of different immunological processes. These processes include, but are not limited to:

(1) Cytokine and chemokine signaling.
(2) Embryonic lymphoid organ development.
(3) Immune cell migration in lymphoid organs.
(4) Immune cell development and differentiation.
(5) Lymphoid stromal cell function.
(6) Innate and adaptive immunity to bacterial and viral infections.
(7) Chronic inflammation and autoimmune disorders, such as inflammatory bowel disease and rheumatoid arthritis.


Keywords: proteoglycans, glycosaminoglycans, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, GAG modifying enzymes, immune response, immunology, inflammation


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