Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37

Abstract

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.

Keywords: IL-37; chemokines; cytokines; inflammation; mast cells; neuropeptides.

Figure 1

Diagrammatic representation of the role of mast cell-derived heparin in the regulation of the activity of IL-37. Activation of caspase 1 in macrophages, in response to TLR activation, leads to cleavage of pro-IL-37 to mature IL-37, both of which are secreted outside the cell and have anti-inflammatory activity. In the tissue microenvironment, mast cells secrete heparin, which interacts with IL-37 and promotes the formation of inactive homodimers. Mast cells also secrete the proteolytic enzyme tryptase, which exists as homotetramer bound to heparin and promotes inflammation by acting on protease-activated receptors (PAR). In the absence of heparin, biologically active tryptase monomers may be able to generate IL-37 forms with increased anti-inflammatory activity. Open arrows = activation; thin arrows = secretion; thick arrows = stimulation; T arrows = inhibition.