Editorial: Targeting signalling pathways in inflammatory diseases

Abstract

Editorial on the Research TopicTargeting signalling pathways in inflammatory diseases Chronic inflammation, characterized by a persistent elevation of circulating proinflammatory cytokines, is associated with the pathogenesis of many non-communicable diseases that cause a worldwide health burden and a reduction in quality of life (1). The identification of possible therapeutic targets implicated in the regulation of inflammation offers the opportunity to limit the dangers associated with an imbalance in the inflammatory response (2). Adaptor proteins represent key signaling molecules that regulate the host's innate immune response to infections, acting as links between receptors and other molecules in several signaling cascades (3,4). The evident importance of these proteins in the pathophysiology of different chronic inflammatory illnesses makes them attractive therapeutic targets (4).Here, we focus on a crucial inflammation-related adaptor of Toll-like receptors (TLR), called MyD88 adaptor-like (MAL) or Toll-interleukin-1 Receptor (TIR) domaincontaining adaptor protein (TIRAP). MAL contains a TIR domain, required for mediating interactions with receptors on the membrane and with downstream signaling molecules (5). MAL represents a key mediator of TLR signaling in immune cells such as macrophages (6, 7), where activation of TLR2 and TLR4 cause persistent inflammation in a MAL-dependent fashion (7). Following receptor-mediated detection of pathogenic ligands, MAL mediates various protein-protein interactions (Figure 1A).Tyrosine kinases, including BTK and PKCd, have a major role in the activation of MAL, with BTK mediating phosphorylation on the four MAL residues Y86, Y106, Y159, and Y187 (5), as well as PKCd phosphorylating Y86 and Y106 in MAL's TIR domain (8). The overlapping phosphorylation sites highlight the possible interconnected activities of these kinases with MAL, as well as pointing to possible context-dependent fine-tuning of MAL activity (8). After activation, MAL interacts with critical inflammatory proteins and eventually activates several transcriptional factors involved in the release of proinflammatory cytokines, which consequently leads to an inflammatory response (5). Contrary to phosphorylation, nitric oxide (NO)-mediated S-nitrosylation of Frontiers in Immunology frontiersin.org 01