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Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, participate in intercellular communication, and particularly, in paracrine and endocrine signalling. The EVs and their specific contents have been considered hallmarks of different diseases. It has been recently discovered that EVs can co-transport nucleic acids such as DNAs, ribosomal RNAs, circular RNAs (circRNAs), long noncoding RNAs (lnRNAs) and microRNAs (miRNAs). miRNAs are important regulators of gene expression at the post-transcriptional level, although they may also play other roles. Recent evidence supports the hypothesis that miRNAs can activate Toll-like receptors (TLRs) under certain circumstances. TLRs belong to a multigene family of immune system receptors and have been recently described in the nervous system. In the immune system, TLRs are important for the recognition of the invading microorganisms, whereas in the nervous system, they recognise endogenous ligands released by undifferentiated or necrotic/injured cells. In the neuronal disease field, TLRs activity has been associated with amyotrophic lateral sclerosis (ALS), stroke, Alzheimer’s and Parkinson’s disease. Herein, we reviewed the current knowledge of the relationship between miRNA release by EVs and the inflammation signalling triggered by TLRs in neighbouring cells or during long-distance cell-to-cell communication. We highlight novel aspects of this communication mechanism, offering a valuable insight into such pathways in health and disease.

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling. Cells in the immune system have proteins at their surface that detect molecules produced by invading microbes. One of these proteins is Toll-like receptor 4, TLR4 for short. Once TLR4 is activated, the immune cells form MyDDosomes – intricate complexes made of many different proteins. These structures form a signal that mobilizes the cell to fight the infection. In particular, the complexes set up a chain of events that leads to a gene-regulating protein getting access to the cell’s DNA. There, the protein switches on genes which produce other proteins important for inflammation, one of the body’s most important tools to fight an infection. The activation of TLR4 is thought to be an all-or-nothing mechanism: the receptors are either ‘on’ or ‘off’. However, different microbial molecules recognized by TLR4 trigger different levels of inflammation, ranging from mild to severe. It remained unclear how an all-or-none response from the frontline receptors could lead to a gradual response from the cell. Here, Latty et al. compare what happens to TLR4, MyDDosomes and the gene-regulating proteins when living immune cells are stimulated by different doses of two microbial molecules. These agents are both recognized by TLR4, but they lead to different levels of inflammation. The type of microbial molecule, or their concentration, does not change how TLR4 is activated. Two TLR4 proteins can loosely associate with each together to form a dimer. When they bind a microbial molecule, the dimer becomes more stable. This changes the shape of the TLR4 proteins, which in turn triggers the formation of a scaffold of MyDDosomes. More stable TLR4 dimers are formed when the cells is in contact with a microbial molecule that triggers a strong immune reaction, and possibly when its concentration is higher. Crucially, the different microbial agents and their concentration levels modify how MyDDosomes assemble. By ‘tagging’ each protein in the complex with a fluorescent chemical, Latty et al. can follow its formation as it actually happens. When the cells are stimulated with microbial molecules that provoke a strong inflammation, the MyDDosomes may be bigger, in greater numbers, and form more quickly. In turn, under strong microbial activation, the gene-regulating protein that switches on the immune response genes goes to the DNA faster and in higher numbers. This suggests that the pace of assembly, the size and the number of MyDDosomes control the strength of the immune response. TLR4 is involved in diseases such as cancer or Alzheimer’s disease, where the body has an incorrect inflammation response. Knowing in greater detail the cellular processes activated by TLR4 could help efforts to find new drug targets for these conditions.

Probiotics, included in functional foods, nutritional supplements, or nutraceuticals, exhibit different beneficial effects on gut function. They are extensively used to improve the digestive processes as well as reduce the symptoms and progression of different diseases. Probiotics have shown to improve dysbiosis and modulate the immune response of the host by interacting with different cell types. Probiotics and the host can interact in a direct way, but it is becoming apparent that communication occurs also through extracellular vesicles (EVs) derived from probiotics. EVs are key for bacteria–bacteria and bacteria–host interactions, since they carry a wide variety of components that can modulate different signaling pathways, including those involved in the immune response. Interestingly, EVs are recently starting to be considered as an alternative to probiotics in those cases for which the use of live bacteria could be dangerous, such as immunocompromised individuals or situations where the intestinal barrier is impaired. EVs can spread through the mucus layer and interact with the host, avoiding the risk of sepsis. This review summarizes the existing knowledge about EVs from different probiotic strains, their properties, and their potential use for the prevention or treatment of different gastrointestinal diseases.

Hidradenitis suppurativa (HS), a chronic inflammatory condition, features recurrent, painful lesions in the perineal area, severely impairing patients' quality of life. Despite its clinical significance, HS pathogenesis remains incompletely understood, and effective treatments are scarce. Interleukin-1 receptor-associated kinase 4 (IRAK4) is located downstream of IL-1R/TLR in the IL-1R/TLR signaling pathway, which is upstream of the end products of the pathway. IRAK4-targeted drugs can potentially block this pathway, reducing cytokine secretion and alleviating HS symptoms. This paper comprehensively reviews IRAK4 and its family members' physiological functions, systematically examines the IRAK family's roles in the IL-1R/TLR pathway, with a focus on IRAK4, analyzes IRAK4's specific role in HS, strengthening the theoretical basis for using IRAK4-targeted drugs. The text also covers representative drugs of the major biologics currently used in the treatment of HS and describes the IRAK4 inhibitor Zimlovisertib and the IRAK4 degrader KT-474, along with a discussion of the current status of drugs that inhibit IRAK4 in the treatment of HS and the challenges they face.

Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.

Systemic lupus erythematosus (SLE) is an autoimmune illness marked by the loss of immune tolerance and the production of autoantibodies against nucleic acids and other nuclear antigens (Ags). B lymphocytes are important in the immunopathogenesis of SLE. Multiple receptors control abnormal B-cell activation in SLE patients, including intrinsic Toll-like receptors (TLRs), B-cell receptors (BCRs), and cytokine receptors. The role of TLRs, notably TLR7 and TLR9, in the pathophysiology of SLE has been extensively explored in recent years. When endogenous or exogenous nucleic acid ligands are recognized by BCRs and internalized into B cells, they bind TLR7 or TLR9 to activate related signalling pathways and thus govern the proliferation and differentiation of B cells. Surprisingly, TLR7 and TLR9 appear to play opposing roles in SLE B cells, and the interaction between them is still poorly understood. In addition, other cells can enhance TLR signalling in B cells of SLE patients by releasing cytokines that accelerate the differentiation of B cells into plasma cells. Therefore, the delineation of how TLR7 and TLR9 regulate the abnormal activation of B cells in SLE may aid the understanding of the mechanisms of SLE and provide directions for TLR-targeted therapies for SLE.

Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes.

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

Several studies have identified mutations in the MYD88L265P gene as a key driver mutation in several B-cell lymphomas. B-cell lymphomas that harbor the MYD88L265P mutation form a complex with phosphorylated Bruton’s tyrosine kinase (BTK) and are responsive to BTK inhibition. However, BTK inhibition in B-cell lymphomas rarely results in a complete response and most patients experience eventual disease relapse. Persistent survival signaling though downstream molecules such as interleukin 1 receptor-associated kinase 4 (IRAK-4), an integral part of the “myddosome” complex, has been shown to be constitutively active in B-cell lymphoma patients treated with BTK inhibitors. Emerging evidence is demonstrating the therapeutic benefit of IRAK-4 inhibition in B-cell lymphomas, along with possibly reversing BTK inhibitor resistance. While MYD88 gene mutations are not present in myeloid malignancies, downstream overexpression of the oncogenic long form of IRAK-4 has been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), particularly in AML and MDS that harbor mutations in splicing factors U2AF1 and SF3B1. These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.

Background Sepsis is more common in the elderly. TNF⍺ is recognized as an important mediator in sepsis and Toll-like receptors (TLRs) play an important role in initiating signaling cascades to produce TNF⍺. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis. Aims and methods We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40–80 years. TNFα production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects ( n  = 250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR. Results and discussion We measured a 2.5% increase per year in basal secretion of TNFα with aging ( n  = 554 p  = 0.02). Likewise, TNFα secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/year; p  = 0.0005) and zymosan A (1.1% increase/year p  = 0.03). We also examined the difference between baseline and stimulated TNFα for each individual. We found that the increase was driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/year; p  = 0.05), lipoteichoic acid (2.1% decrease/year p  = 0.03), and Pam3CysK (2.6% decrease/year p  = 0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFα production. Conclusions With aging, circulating leukocytes produce high levels of TNFα at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults.