Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that ...delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges.
TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen‐associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling ...cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR‐ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.
Review on the importance of TLR4 and TLR9 dynamic subcellular localization in the inflammatory responses.
Nanoparticles represent a new generation of drug delivery systems that can be engineered to harness optimal target selectivity for specific cells and tissues and high drug loading capacity, allowing ...for improved pharmacokinetics and enhanced bioavailability of therapeutics. The spontaneous propensity of both organic and colloidal nanoparticles to be captured by the cells of the reticuloendothelial system encouraged their utilization as passive targeting systems that can be preferentially directed to innate immune cells, such as macrophages, dendritic cells and neutrophils. The natural affinity for phagocytic cells suggests the possible implementation of nanoparticles as an immunotherapeutic platform for inflammatory diseases and autoimmune disorders. Here we discuss the recent advances in the application of nanotechnology to induce antigen-specific tolerance in autoimmunity and the use of nanoparticles for anti-inflammatory therapies, including treatment of inflammatory bowel diseases, psoriasis and rheumatoid arthritis.
Type III interferons (IFNs) (or IFN-λ) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each ...can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many
models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings.
A heterogeneous mixture of lipids called oxPAPC, derived from dying cells, can hyperactivate dendritic cells (DCs) but not macrophages. Hyperactive DCs are defined by their ability to release ...interleukin-1 (IL-1) while maintaining cell viability, endowing these cells with potent aptitude to stimulate adaptive immunity. Herein, we found that the bacterial lipopolysaccharide receptor CD14 captured extracellular oxPAPC and delivered these lipids into the cell to promote inflammasome-dependent DC hyperactivation. Notably, we identified two specific components within the oxPAPC mixture that hyperactivated macrophages, allowing these cells to release IL-1 for several days, by a CD14-dependent process. In murine models of sepsis, conditions that promoted cell hyperactivation resulted in inflammation but not lethality. Thus, multiple phagocytes are capable of hyperactivation in response to oxPAPC, with CD14 acting as the earliest regulator in this process, serving to capture and transport these lipids to promote inflammatory cell fate decisions.
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•CD14 endocytosis upon oxPAPC binding prevents inflammation via TLR4•CD14 endocytosis upon oxPAPC binding promotes inflammation via caspase-1 and -11•oxPAPC and its components induce IL-1 release from living (hyperactive) phagocytes•Conditions of cell hyperactivation induce non-lethal inflammatory sepsis in mice
Inflammasomes elicit pyroptosis or cell hyperactivation, with the latter defined as living cells that release IL-1. Zanoni et al. report that CD14 captures distinct lipids within oxPAPC to promote dendritic cell and/or macrophage hyperactivation. Unlike pyroptotic stimuli, oxPAPC lipids promote long-term IL-1 release from cells and non-lethal inflammation in mice.
Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic ...production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.
CD14 is a glycosylphosphatidylinositol (GPI)-anchored receptor known to serve as a co-receptor for several Toll-like Receptors (TLRs) both at the cell surface and in the endosomal compartment. CD14 ...can be expressed by cells of both hematopoietic and non-hematopoietic origin as a cell membrane or secreted protein. Although CD14 was discovered more than 20 years ago, its activities remain largely to be defined. Most of the information available concerns CD14's role as a co-receptor working with TLR4 and facilitating cellular responses to low doses of lipopolysaccharide (LPS). Recent studies have highlighted and molecularly defined many other functions of this pattern recognition receptor (PRR). These functions include the mechanisms through which CD14 allows the activation of the TLR4-TRAM-TRIF pathway upon LPS stimulation; the capacity of CD14 to transduce a TLR4-independent signaling pathway leading to the activation of NFAT transcription factor family members with important consequences in myeloid cells; the CD14 influence on cell metabolism in conditions predisposing to obesity. In this review, we summarize recent progresses toward the molecular definition of the multiple roles exerted by CD14 in innate immune cells in response to LPS and the consequences of CD14 activation in physiologic and pathologic conditions.
Humans are constantly exposed to fungi, either in the form of commensals at epithelial barriers or as inhaled spores. Innate immune cells play a pivotal role in maintaining commensal relationships ...and preventing skin, mucosal, or systemic fungal infections due to the expression of pattern recognition receptors that recognize fungal cell wall components and modulate both their activation status and the ensuing adaptive immune response. Commensal fungi also play a critical role in the modulation of homeostasis and disease susceptibility at epithelial barriers. This review will outline cellular and molecular mechanisms of anti‐fungal innate immunity focusing on C‐type lectin receptors and their relevance in the context of host‐fungi interactions at skin and mucosal surfaces in murine experimental models as well as patients susceptible to fungal infections.
C‐type lectin receptor (CLR) mediated recognition of fungi by innate immune cells at the epithelial barriers prevents recurrent fungal infections and establishes host‐fungi commensal relationships. These concepts have been demonstrated in mouse models and patients with primary immunodeficiencies affecting the function of CLRs (e.g. dectin‐1) or their signaling molecules (e.g. CARD9).
Toll-like receptors (TLRs) are essential players in the innate immune response to invading pathogens. Although extensive research efforts have provided a considerable wealth of information on how ...TLRs function, substantial gaps in our knowledge still prevent the definition of a complete picture of TLR signaling. However, several recent studies describe additional layers of complexity in the regulation of TLR ligand recognition, adaptor recruitment, posttranslational modifications of signaling proteins, and the newly described, autonomous role of the TLR4 co-receptor CD14. In this review, by using it as model system for the whole TLR family, we attempt to provide a complete description of the signal transduction pathways triggered by TLR4, with a particular emphasis on the molecular and cell biological aspects regulating its function. Finally, we discuss a recently reported model of CD14-dependent signaling and highlight its biological implications.
With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field ...of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.
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