Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α ...and IFN-β) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transcription factors IRF3 or IRF7. IFN-β production after fungal infection was recently reported, although the underlying mechanism remains controversial. Here we describe that IFN-β production by dendritic cells (DCs) induced by Candida albicans is largely dependent on Dectin-1- and Dectin-2-mediated signaling. Dectin-1-induced IFN-β production required the tyrosine kinase Syk and the transcription factor IRF5. Type I IFN receptor-deficient mice had a lower survival after C. albicans infection, paralleled by defective renal neutrophil infiltration. IFN-β production by renal infiltrating leukocytes was severely reduced in C. albicans-infected mice with Syk-deficient DCs. These data indicate that Dectin-induced IFN-β production by renal DCs is crucial for defense against C. albicans infection.
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•IFN-β production in response to Candida is mainly controlled by Dectin-1 signaling•Dectin-1 triggers IFN-β production by a Syk-Card9-IRF5-dependent pathway•IFNAR deficiency reduces renal neutrophil influx and survival after Candida infection•Renal IFN-β production during Candida infection mainly relies on DCs and Syk signaling
Despite the crucial role of tissue-resident memory T (Trm) cells in protective immunity, their priming remains poorly understood. Here, we have shown differential priming requirements for Trm versus ...circulating memory CD8+ T cells. In vaccinia cutaneous-infected mice, DNGR-1-mediated crosspresentation was required for optimal Trm cell priming but not for their skin differentiation or for circulating memory T cell generation. DNGR-1+ dendritic cells (DCs) promoted T-bet transcription-factor induction and retention of CD8+ T cells in the lymph nodes (LNs). Inhibition of LN egress enhanced Trm cell generation, whereas genetic or antibody blockade of DNGR-1 or specific signals provided during priming by DNGR-1+ DCs, such as interleukin-12 (IL-12), IL-15, or CD24, impaired Trm cell priming. DNGR-1 also regulated Trm cell generation during influenza infection. Moreover, protective immunity depended on optimal Trm cell induction by DNGR-1+ DCs. Our results reveal specific priming requirements for CD8+ Trm cells during viral infection and vaccination.
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•Distinct priming requirements of Trm versus circulating memory in viral infection•Genetic or antibody blockade of crosspriming selectively impairs Trm generation•Unique signals from DNGR-1+ DC induce T-bet and retain naive T cells for LN priming•Protective mucosal immunity depends on optimal Trm induction by DNGR-1+ DC
Priming of tissue-resident memory T cells (Trm) is not well characterized. Iborra et al. find that prolonged antigen crosspresentation in combination with specific signals from DNGR-1+ dendritic cells are required for optimal Trm priming but not for their differentiation, and are dispensable for the generation of circulating memory T cells.
Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the ...gene
, which senses tissue damage and favors cross-presentation of dead-cell material to CD8
T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic
infection without affecting fungal burden. This effect is B and T cell-independent and attributable to increased neutrophilia in DNGR-1-deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by
) production by cDC1s during
infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1-mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.
Endotoxin tolerance was first described in a study that exposed animals to a sublethal dose of bacterial endotoxin. The animals subsequently survived a lethal injection of endotoxin. This refractory ...state is associated with the innate immune system and, in particular, with monocytes and macrophages, which act as the main participants. Several mechanisms are involved in the control of endotoxin tolerance; however, a full understanding of this phenomenon remains elusive. A number of recent reports indicate that clinical examples of endotoxin tolerance include not only sepsis but also diseases such as cystic fibrosis and acute coronary syndrome. In these pathologies, the risk of new infections correlates with a refractory state. This review integrates the molecular basis and clinical implications of endotoxin tolerance in various pathologies.
β-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost ...trained immunity remain undefined. We found that β-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysMΔSHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following β-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysMΔSHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge in vivo and were better protected against Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against Candida infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1.
Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a ...role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology.
Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology.
The C-type lectin receptor Dectin-1 was originally described as the β-glucan receptor expressed in myeloid cells, with crucial functions in antifungal responses. However, over time, different ligands ...both of microbial-derived and endogenous origin have been shown to be recognized by Dectin-1. The outcomes of this recognition are diverse, including pro-inflammatory responses such as cytokine production, reactive oxygen species generation and phagocytosis. Nonetheless, tolerant responses have been also attributed to Dectin-1, depending on the specific ligand engaged. Dectin-1 recognition of their ligands triggers a plethora of downstream signaling pathways, with complex interrelationships. These signaling routes can be modulated by diverse factors such as phosphatases or tetraspanins, resulting either in pro-inflammatory or regulatory responses. Since its first depiction, Dectin-1 has recently gained a renewed attention due to its role in the induction of trained immunity. This process of long-term memory of innate immune cells can be triggered by β-glucans, and Dectin-1 is crucial for its initiation. The main signaling pathways involved in this process have been described, although the understanding of the above-mentioned complexity in the β-glucan-induced trained immunity is still scarce. In here, we have reviewed and updated all these factors related to the biology of Dectin-1, highlighting the gaps that deserve further research. We believe on the relevance to fully understand how this receptor works, and therefore, how we could harness it in different pathological conditions as diverse as fungal infections, autoimmunity, or cancer.
Type-I conventional dendritic cells (cDC1s) are key in inducing adaptive immunity. Using single-cell sequencing, Ginhoux and colleagues (Immunity 2019;50:1069–1083.e8) find that a subset of activated ...cDC1s in bacteria-infected skin is critical for neutrophil recruitment via the production of VEGF-α. These results reveal a crucial function for cDC1s beyond antigen presentation.
Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil ...emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine “depot” in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.
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•The CXCR2 ligands CXCL1 and CXCL2 play distinct roles in neutrophil diapedesis•Endothelial cell (EC)- and pericyte-derived CXCL1 mediate neutrophil crawling•CXCL2 is neutrophil derived and is retained at EC junctions by ACKR1•ACKR1-CXCL2 axis is critical for unidirectional paracellular neutrophil TEM in vivo
Girbl et al. find that sequential interactions with the chemokines CXCL1 and CXCL2 guide neutrophil crawling and subsequent migration through venular walls during inflammation. Transmigrating neutrophils promoted unidirectional luminal-to-abluminal migration by depositing CXCL2 on the chemokine receptor ACKR1 at endothelial junctions, providing a paradigm of self-guided migration.
According to a large number of reported cohorts, sepsis has been observed in nearly all deceased patients with COVID-19. We and others have described sepsis, among other pathologies, to be an ...endotoxin tolerance (ET)-related disease. In this study, we demonstrate that the culture of human blood cells from healthy volunteers in the presence of SARS-CoV-2 proteins induced ET hallmarks, including impairment of proinflammatory cytokine production, low MHC class II (HLA-DR) expression, poor T cell proliferation, and enhancing of both phagocytosis and tissue remodeling. Moreover, we report the presence of SARS-CoV-2 blood circulating proteins in patients with COVID-19 and how these levels correlate with an ET status, the viral RNA presence of SARS-CoV-2 in plasma, as well as with an increase in the proportion of patients with secondary infections.
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