Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases

Abstract

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Despite the tremendous progress in the treatment of eosinophilic disorders with the implementation of biologics, there is an unmet need for novel therapies that specifically target the cytotoxic effector functions of eosinophils without completely depleting this multifunctional immune cell type. Recent studies have uncovered several endogenous molecules that decrease eosinophil migration and activation. These include short chain fatty acids (SCFAs) such as butyrate, which are produced in large quantities in the gastrointestinal tract by commensal bacteria and enter the systemic circulation. In addition, high-density lipoprotein-associated anti-inflammatory apolipoproteins have recently been shown to attenuate eosinophil migration and activation. Here, we focus on the anti-pathogenic properties of SCFAs and apolipoproteins on eosinophil effector function and provide insights into the potential use of SCFAs and apolipoproteins (and their mimetics) as effective agents to combat eosinophilic inflammation.

Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins

“…In coronary artery disease patients, an inverse association of absolute eosinophil count and HDL cholesterol and a positive association with the prevalence of coronary artery disease was reported [ 250 ]. Both HDL and HDL apolipoproteins were recently shown to effectively inhibit eosinophil chemotaxis [ 29 ] and to attenuate eosinophil activation [ 251 ]. In a study involving atopic dermatitis patients, patients’-derived HDL showed an impaired ability to inhibit agonist-induced eosinophil shape change and migration compared to HDL isolated from healthy controls [ 34 ].…”

Anti-Inflammatory Function of Fatty Acids and Involvement of Their Metabolites in the Resolution of Inflammation in Chronic Obstructive Pulmonary Disease

“…The entry of SCFAs into the systemic bloodstream may be due both to passive diffusion and to the participation of special transporters, such as monocarboxylate transporter 1 (MCT1) and sodium-bound monocarboxylate transporter 1 (SMCT1) [ 198 ]. MCT1 has also been detected in cells of the immune system, including lymphocytes, monocytes, and neutrophils [ 210 , 211 ].…”

“…SCFAs are thought to realize their action through inhibition of histone deacetylase (HDAC) and through interaction with the G-protein-related receptors GPR43 and GPR41, also known as free fatty acid receptor (FFA)2 and FFA3, respectively [ 211 , 212 , 213 , 214 ]. In addition, the receptors for SCFAs are GPR109a (also known as HCA2) and olfactory receptor 78 (Olfr78) [ 215 , 216 , 217 ].…”

“…In addition, the receptors for SCFAs are GPR109a (also known as HCA2) and olfactory receptor 78 (Olfr78) [ 215 , 216 , 217 ]. GPR43 is expressed in immune cells, including neutrophils, monocytes, and lymphocytes [ 211 , 212 , 213 , 218 ].…”

“…Butyrate, acetate, and propionate are considered to be histone deacetylases (HDAC) inhibitors, which are a class of enzymes that inhibit transcription through the removal of acetyl groups from chromatin [ 211 , 219 ]. Because of this, they are involved in the regulation of many cellular functions such as migration [ 211 , 220 , 221 ] and survival [ 211 , 222 , 223 ].…”