Candida albicans β-Glucan Differentiates Human Monocytes Into a Specific Subset of Macrophages

Abstract

β-Glucan derived from cell walls of Candida albicans is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.

Monocytes and the Host Response to Fungal Pathogens

“…Upon rechallenge with a lethal infection of C. albicans, these trained monocytes and macrophages had enhanced cytokine production and improved survival of the infected mice (Browder et al, 1984;Quintin et al, 2012). These host protective effects were confirmed to take place in the absence of T and B cells (Bistoni et al, 1986;Leonhardt et al, 2018). The trained cells also had stronger responses upon restimulation with other microbial antigens and pathogens, including lipopolysaccharide (LPS) and Staphylococcus aureus (Di Luzio and Williams, 1978;Quintin et al, 2012;Marakalala et al, 2013).…”

The Potential Effects of Short-Chain Fatty Acids on the Epigenetic Regulation of Innate Immune Memory

“…Trained immunity arises when some microbial and vaccine antigens cause monocytes/macrophages to make an adaptative response to secondary challenge by increasing their proinflammatory cytokine response to a broad range of microbial stimuli, also known as heterologous protection. This pathogen-agnostic immunity underpins the nonspecific protective effects of the BCG vaccine, among others [37][38][39]. Trained immunity is dependent on epigenetic remodelling and changes in intracellular metabolic pathways.…”

Could the Induction of Trained Immunity by β-Glucan Serve as a Defense Against COVID-19?

“…As Netea et al points out in his excellent recent review article on TIRIM, models of TRIM using various training agents have shown protection against a host of relevant lethal pathogens such as Streptococcus pneumonia, Toxoplasma gondii, Escherichia coli , and rotavirus ( 43 – 46 ). Further, the various examples of the BCG vaccine and β-glucan affording protection against secondary infections, such as Candida albicans , in a macrophage specific manner, ultimately leads to the idea that the exposure of innate immune cells, specifically myeloid cells, to specific training stimuli results in a non-specific immune protection ( 7 , 9 , 17 , 47 , 48 ).…”