ReviewBruton’s tyrosine kinase (Btk)—the critical tyrosine kinase in LPS signalling?
Introduction
The innate immune response has evolved to recognise structures that are characteristic of microbial pathogens and does so by means of germline encoded pathogen recognition receptors. Recognition of microbial products by receptors on effector cells such as neutrophils, monocytes and macrophages, results in the induction of pro-inflammatory cytokines and activation of the inflammatory response. Toll-like receptors (TLR) are a family of pathogen recognition receptors that discriminate between diverse microbial signatures. To date, genes encoding 10 TLRs have been found in the human genome, each recognising distinct microbial ligands (Fig. 1a). They are characterised as having leucine-rich repeats extracellularly and signal via a conserved intracellular domain that they share with the interleukin-1 (IL-1) receptor family—the Toll/IL-1 receptor (TIR) domain. Of the 10 human TLR members, ligands for all but TLR10 have been described, with TLR2 recognising peptidoglycan, TLR3 recognising double stranded viral RNA and TLR9 recognising bacterial hypomethylated DNA motifs, for example (reviewed in [1]). The discovery that TLR4 was the long sought after signalling component of the lipopolysaccharide (LPS) receptor complex (composed of CD14 and MD2 on myeloid cells) has resulted in intense research into how signalling pathways are regulated downstream of TLR4.
A key consequence of LPS signalling in cells is the induction of pro-inflammatory cytokines such as TNFα and IL-1, via activation of the transcription factor NFκB. The pathway to NFκB activation in response to LPS has been characterised in molecular detail, resulting in the discovery of a novel family of TIR domain-containing adapter proteins, which serve to regulate and fine tune TLR responses [2]. The first identified member of this adapter family was MyD88 [3]. MyD88 has an N terminal death domain and a C terminal TIR domain. In brief, many of the TLRs recruit MyD88 to their intracellular domains once activated. The death domain of MyD88 subsequently recruits the death-domain-containing serine/threonine kinases, IRAK-1 and IRAK-4. These function to activate the downstream adapter protein TRAF-6, which links TIR-domain-containing receptors to the IκB kinase (IKK) complex regulating NFκB activation (reviewed in [4], [5]). The importance of MyD88 in TLR signalling has been demonstrated by the inability of MyD88-deficient mice to respond appropriately to a variety of TLR ligands, namely LPS, peptidoglycan and bacterial CpG motifs [6], [7].
Interestingly, analysis of MyD88-deficient cells demonstrates that MyD88-independent pathway exists regulating late NFκB activation and the induction of IRF-3-dependent genes in response to LPS. This observation has given rise to the discovery and characterisation of two additional TIR domain-containing adapters, Mal (MyD88-adapter like) and Trif (TIR-containing adaptor-inducing IFN-β). Mal appears to be specific for TLR2 and TLR4 signalling and was initially thought to lie on the MyD88-independent pathway [8], [9]. However, Mal knockout mice have demonstrated that, like MyD88, Mal regulates MyD88-dependent signals such as those leading to NFκB activation and pro-inflammatory cytokine production, possibly via its ability to interact with MyD88 [10], [11]. The third adapter identified, Trif (also known as TICAM-1), interacts with TLR3 and mediates TLR3-dependent induction of IFN-β via NFκB and IRF-3 activation [12], [13]. Trif is also involved in the MyD88-independent pathway activated by TLR4. Meanwhile, a fourth adapter has recently been characterised, TRAM (TRIF-related adaptor molecule), which, unlike any of the other adaptors, is specific for TLR4 signalling and regulates the MyD88-independent pathway to NFκB and IRF-3 activation [14]. It also regulates late NFκB activation in response to TLR4 (summarised in Fig. 1b) [15]. Thus it appears that TLRs use different combinations of adaptor proteins in order to mount an appropriate response to specific microbial pathogens. These recent discoveries have important implications for other downstream events that occur following LPS stimulation, particularly tyrosine kinase activation and it is this aspect of LPS signalling which will form the focus of this review.
Section snippets
Src kinases and LPS signalling
Non-receptor tyrosine kinases are involved in signalling in response to diverse stimuli, but are perhaps most studied in the context of immune regulation. They are typified by the Src kinase family of protein tyrosine kinases (PTK), which are best understood for their role downstream of receptors such as the T cell receptor (TCR) and B cell receptor (BCR). Ligation of either of these receptors activates the Src family members associated with them, a consequence of which is trans-phosphorylation
Btk and NFκB activation
Functionally Btk is critically important for the growth and differentiation of cells of the hematopoietic lineage. Its expression is limited to B cells, mast cells and myeloid cells but its signalling functions have been examined mainly in the context of B cells, particularly in relation to B cell receptor signalling. One of the key consequences of BCR stimulation is activation of the transcription factor NFκB and consequent induction of genes regulating cell survival and proliferation. NFκB is
Future perspectives
A particularly important aspect of the role of Btk in immune function is the inability of B cells from Xid mice to mount a T-cell-independent type II (TI-2) response. TI-2 antigens are those that are expressed on the surface of pathogens in an organised, highly repetitive form (such as LPS) and can activate specific B cells in a T-cell independent manner by cross-linking antigen receptors in a multivalent fashion. While this first signal of multivalent mIg cross-linking can induce B-cell
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2021, Biomedicine and PharmacotherapyCitation Excerpt :Taken together, these results strengthen the conclusion that FAK1, ALK, and to a lesser degree Axl, control part of the LPS inflammatory signalling pathway in EC and are thus therapeutic targets of interest. Since LPS-mediated endothelial activation is largely NF-κB driven [11,21], and several TKs have been linked to NF-κB activation [15,20], we investigated whether pharmacological inhibition of FAK1 and ALK would alter NF-κB activation status in LPS-stimulated EC. Immunoblotting of HUVEC lysates showed reduced IκB-α protein following 30 and 60 min of LPS stimulation compared to unstimulated controls (Fig. 6A).
Inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic strategy
2019, Pharmacological ResearchCitation Excerpt :BTK and ITK in their inactive forms are present in the cytoplasm but on activation, they migrate to the cell membrane [6,7]. Upon activation, BTK/ITK gets phosphorylated thereby causing induction of downstream events like the proliferation/differentiation in innate (neutrophils) and adaptive (B/T cells) immune cells through numerous transcription factors, e.g., NFκB, NFAT, STAT3, etc. [6,8–10]. On this basis, both of these kinases are important biological targets for therapeutic intervention in many disorders which include inflammatory diseases and B cell malignancies.
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2011, European Journal of PharmacologyCitation Excerpt :Lee et al. (2005) also found that Src was involved in NF-κB activation by LPS in RAW264.7 cells by using Src inhibitor PP1. Furthermore, Jefferies and O'Neill (2004) claimed that Btk is a critical tyrosine kinase in LPS signaling. Syk is best known as a critical component of immunoreceptor signaling in leukocytes and regulates pro-inflammatory responses induced by TNF and TLR stimulation (Turner et al., 2000; Lin et al., 2010; Chaudhary et al., 2007).
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