The role of hyaluronan synthesis and degradation in the critical respiratory illness COVID-19

Abstract

Hyaluronan (HA) is a polysaccharide found in all tissues as an integral component of the extracellular matrix (ECM) that plays a central regulatory role in inflammation. In fact, HA matrices are increasingly considered as a barometer of inflammation. A number of proteins specifically recognize the HA structure and these interactions modify cell behavior and control the stability of the ECM. Moreover, inflamed airways are remarkably rich with HA and are associated with various inflammatory diseases including cystic fibrosis, influenza, sepsis, and more recently coronavirus disease 2019 (COVID-19). COVID-19 is a worldwide pandemic caused by a novel coronavirus called SARS-CoV-2, and infected individuals have a wide range of disease manifestations ranging from asymptomatic to severe illness. Critically ill COVID-19 patient cases are frequently complicated by development of acute respiratory distress syndrome (ARDS), which typically leads to poor outcomes with high mortality rate. In general, ARDS is characterized by poor oxygenation accompanied with severe lung inflammation, damage, and vascular leakage and has been suggested to be linked to an accumulation of HA within the airways. Here, we provide a succinct overview of known inflammatory mechanisms regulated by HA in general, and those both observed and postulated in critically ill patients with COVID-19.

Keywords: ARDS; COVID-19; coronavirus; hyaluronan; inflammation.

Figure 1.

Model for synthesis and degradation of HA. Hyaluronan is synthesized by membrane-bound synthases (HAS) on the inner surface of the plasma membrane, and the chains are extruded through pore-like structures into the extracellular space. The HA synthases HAS 1–3 produce HA in the plasma membrane of different sizes and rates. The catabolism of HA and hence the molecular weight distribution is predominantly regulated by the hyaluronidase (HYALs) family, Hyal-1 and Hyal-2. In recent years, newly discovered HA degrading proteins were also identified. The cell migration inducing protein (CEMIP), also known as KIAA1199, mediates the intracellular degradation of HA whereas the transmembrane protein 2 (Tmem2) controls the extracellular degradation. HA and fragments may bind to many different hyaladherins in the extracellular matrix, on the cell surface and intracellularly such as CD44, RHAMM, TSG-6, and inter-α-inhibitor heavy chains. HA, hyaluronan.

Figure 2.

Schematic representation of known and suggested roles of HA in COVID-19 and ARDS. Viral infection may directly promote HA synthesis, and IL-13 is a known activator of HAS1 in COVID-19. Accumulation of HA promotes and sustains immune cell recruitment into the lung. Homeostatic HMW-HA becomes degraded by hyaluronidases in concert with reactive oxygen species by infiltrating neutrophils. Generation of LMW-HA fragments activate alveolar macrophages and induce the release of inflammatory cytokines (e.g., IL-6, IL-8, IL-10, and interferon-α), chemokines (e.g., IP-10 and MCP1), and growth factors by several cell types including alveolar epithelial cells. These proinflammatory LMW-HA fragments boost the effect of the cytokine storm by stimulating the release of more cytokines from immune and alveolar cells leading to hyperinflammatory syndrome. HA fragments generated during COVID-19 can directly promote endothelial barrier permeability. The edematous alveoli develop hypoxia as dysregulated HA synthesis and degradation proceed unchecked, leading to accumulation of HA within respiratory fluids, alveolar collapse, and ARDS. ARDS, acute respiratory distress syndrome; HA, hyaluronan; LMW-HA, low-molecular-weight hyaluronan.