Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection

Abstract

Summaryβ-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost trained immunity remain undefined. We found that β-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysMΔSHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following β-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysMΔSHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge in vivo and were better protected against Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against Candida infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1.

Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages

“…To this end, a well-established in vitro culture of macrophages derived from the head kidney (21), the fish equivalent to mammalian bone marrow, was adapted to study the mechanisms of trained immunity in the common carp. Recent studies have shown trained immunity in monocytes and in bone marrow-derived macrophages (3,22) and even comparable trained immunity profiles between these two cell populations (23). These findings support the use of a heterogeneous myeloid primary cell culture, such as the head kidney-derived macrophage culture in carp.…”

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…Herein, we show that the inhibition of PM‐induced mTOR signalling and the reduction in PD‐L1 expression in DCs by alum correlate with a reduction on the generation of FOXP3 + Treg cells. Supporting this view, SH2 domain‐containing inositol 5’‐phosphatase (SHIP)‐deficient mice, in which the Akt/mTOR pathway is upregulated on myeloid cells, show a remarkable increase in FOXP3 + Treg cells …”

Defining trained immunity and its role in health and disease

“…The upregulation of miR-155 during inflammatory processes has also been correlated with the hyperactivation of cells from the myeloid compartment. This is likely owing to a decreased activity of phosphatases that act as negative regulators of a series of intracellular pathways 121 , including the phosphatase SHIP1, which was recently demonstrated to act as a negative regulator in the induction of trained immunity 122 .…”