The Exploitation of the Glycosylation Pattern in Asthma: How We Alter Ancestral Pathways to Develop New Treatments

Abstract

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment.

Keywords: asthma; biomarkers; chitotriosidase 1; glycobiology; glycosylation.

Figure 1

Changes in protein glycosylation shape the immune cells’ function and trafficking in asthma. The activation of Th-2 lymphocytes by dendritic cells (DC) leads to cytokine production and Th-2 cell expansion. IL-13 prompts the overgrowth of smooth muscle cells (SMCs), modifies functions of alveolar macrophages (MAs), and leads to the fucosylation of epithelial surface proteins. Due to the immune response, the hyperproduction of mucus occurs and affects the MUC5AC/MUC5B ratio. At the same time, IL-4 supports B cells in antibody production, which are also modified by glycans. Chemokine production increases the influx of myeloid cells, including monocytes (MOs) and neutrophils (NEUs). Modification by glycosylation receptors affects the cell’s trafficking (CD44 and Mac-1), function (TCR and CD25), and metabolism (Glut1).