Toll-like receptors (TLRs) are danger-sensing receptors that typically propagate self-limiting inflammatory responses, but can unleash uncontrolled inflammation in non-homeostatic or disease settings. Activation of TLRs by pathogen- and/or host-derived stimuli triggers a range of signalling and transcriptional pathways to programme inflammatory and anti-microbial responses, including the production of a suite of inflammatory cytokines and other mediators. Multiple sorting and signalling adaptors are recruited to receptor complexes on the plasma membrane or endosomes where they act as scaffolds for downstream signalling kinases and effectors at these sites. So far, seven proximal TLR adaptors have been identified: MyD88, MAL, TRIF (also known as TICAM1), TRAM (TICAM2), SARM (SARM1), BCAP (PIK3AP1) and SCIMP. Most adaptors tether directly to TLRs through homotypic Toll/interleukin-1 receptor domain (TIR)–TIR interactions, whereas SCIMP binds to TLRs through an atypical TIR–non-TIR interaction. In this Review, we highlight the key roles for these adaptors in TLR signalling, scaffolding and receptor sorting and discuss how the adaptors thereby direct the differential outcomes of TLR-mediated responses. We further summarise TLR adaptor regulation and function, and make note of human diseases that might be associated with mutations in these adaptors.

In innate immune cells, pathogens and danger signals activate Toll-like receptors (TLRs), unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SCIMP, interacts with TLR4 via direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4 phosphorylation and activation. Consequently, SCIMP is able to direct selective production of the pro-inflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members. We report here that SCIMP is phosphorylated and activated in response to agonists of multiple TLRs, including TLR2, TLR3, TLR4 and TLR9. SCIMP also interacts with TLRs that are known to signal from both the cell surface and endosomal compartments. In so doing, this transmembrane adaptor presents Lyn, along with other effectors such as Grb2, Csk and SLP65, to multiple TLRs during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages alters TLR signalling outputs and the production of IL-6 and IL-12p40 downstream of multiple TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFN, being SCIMP-dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine kinase and its effectors to enable responses against a wide range of danger signals.

Extracellular signal-related kinases 1 and 2 (ERK1/2) are the final components of the mitogen-activated protein kinase (MAPK) phosphorylation cascade, an integral module in a diverse array of signalling pathways for shaping cell behaviour and fate. More recently, studies have shown that ERK1/2 plays an essential role downstream of immune receptors to elicit inflammatory gene expression in response to infection and cell or tissue damage. Much of this work has studied ERK1/2 activation in Toll-like receptor (TLR) pathways, providing mechanistic insights into its recruitment, compartmentalisation and activation in cells of the innate immune system. In this review, we summarise the typical activation of ERK1/2 in growth factor receptor pathways before discussing its known roles in immune cell signalling with a focus downstream of TLRs. We examine emerging research uncovering evidence of dysfunctional ERK1/2 signalling in inflammatory diseases and discuss the potential therapeutic benefit of targeting ERK1/2 pathways in inflammation.

Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro-and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.

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Mutations in LRRK2 are the most common cause of dominantly inherited Parkinson's disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of α-synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein

TLRs engage numerous adaptor proteins and signaling molecules, enabling a complex series of post-translational modifications (PTMs) to mount inflammatory responses. TLRs themselves are post-translationally modified following ligand-induced activation, with this being required to relay the full spectrum of proinflammatory signaling responses. Here, we reveal indispensable roles for TLR4 Y672 and Y749 phosphorylation in mounting optimal LPS-inducible inflammatory responses in primary mouse macrophages. LPS promotes phosphorylation at both tyrosine residues, with Y749 phosphorylation being required for maintenance of total TLR4 protein levels and Y672 phosphorylation exerting its pro-inflammatory effects more selectively by initiating ERK1/2 and c-FOS phosphorylation. Our data also support a role for the TLR4-interacting membrane proteins SCIMP and the SYK kinase axis in mediating TLR4 Y672 phosphorylation to permit downstream inflammatory responses in murine macrophages. The corresponding residue in human TLR4 (Y674) is also required for optimal LPS signaling responses. Our study, thus, reveals how a single PTM on one of the most widely studied innate immune receptors orchestrates downstream inflammatory responses.