The S100 Protein Family as Players and Therapeutic Targets in Pulmonary Diseases

Abstract

The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.

Repurposing Multiple-Molecule Drugs for COVID-19-Associated Acute Respiratory Distress Syndrome and Non-Viral Acute Respiratory Distress Syndrome via a Systems Biology Approach and a DNN-DTI Model Based on Five Drug Design Specifications

“…S100A1 has been reported to contribute to hypoxia-induced inflammation in an earlier study. Although predominantly expressed in cardiomyocytes, S100A1 is also present in lung endothelium and its increased serum level has been documented in several pulmonary diseases [ 116 , 117 , 118 , 119 ]. The other ligand found to stimulate receptor TLR4 also includes lipopolysaccharide (LPS), which is the most studied molecule that constitutes the outer membrane of Gram-negative bacteria.…”

Human‐host transcriptomic analysis reveals unique early innate immune responses in different sub‐phenotypes of COVID‐19

“…The upregulation of IL1R2, HSPA1A, NLRP3, S100A2 and NOS2 in moderate patients plausibly indicates a closely regulated antiviral innate immune response that provides protection from SARS‐CoV‐2 infection and prevents the hyperinflammatory response. 4 , 5 , 6 The DEGs of the mortality group (versus mild/moderate/severe) were functionally different and showed overall decreased expression. Of significant interest was the downregulation of MAL (MYD88 adaptor‐like), an integral component of Toll‐like receptor (TLR) signalling during pathogen invasion, 7 and TRIM16 , which regulates inflammasome activity through NLRP1‐dependent production of IL‐1B (Interleukin) and IL‐18.…”

RAGE pathway activation and function in chronic kidney disease and COVID-19

“…S100 proteins are a family of small calcium-binding cytoskeletal proteins, forming hetero- or homo-dimers, that are released upon cellular activation or apoptosis. Although RAGE is the most common receptor for many of the 25 different known S100 proteins, additional receptors can bind select S100 proteins and induce inflammatory cell signals ( 124 ). Two S100 protein-binding receptors, CD147 ( 125 ) and Toll-like receptor (TLR)-4 ( 126 ), are also indicated to bind the SARS-CoV-2 spike protein in some studies.…”

“…Two S100 protein-binding receptors, CD147 ( 125 ) and Toll-like receptor (TLR)-4 ( 126 ), are also indicated to bind the SARS-CoV-2 spike protein in some studies. RAGE, CD147, and TLR4 all bind the S100 protein, S100A9 ( 124 ). Further work is needed to conclusively establish the role of these three cell surface receptors in SARS-CoV2 pathogenesis, and host defense.…”

“…S100B binds RAGE and fibroblast growth factor receptor (FGFR)-1 ( 124 ) and is expressed in glial cells, dendritic cells, lymphocytes, and adipocytes ( 132 ). Serum S100B is a biomarker for cognitive impairment in patients with ESKD ( 133 ) and also an indicator of COVID-19 severity ( 132 ).…”