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Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira spp. All vertebrate species can be infected; humans are sensitive hosts whereas other species, such as rodents, may become long-term renal carrier reservoirs. Upon infection, innate immune responses are initiated by recognition of Microbial Associated Molecular Patterns (MAMPs) by Pattern Recognition Receptors (PRRs). Among MAMPs, the lipopolysaccharide (LPS) is recognized by the Toll-Like-Receptor 4 (TLR4) and activates both the MyD88-dependent pathway at the plasma membrane and the TRIF-dependent pathway after TLR4 internalization. We previously showed that leptospiral LPS is not recognized by the human-TLR4, whereas it signals through mouse-TLR4 (mTLR4), which mediates mouse resistance to acute leptospirosis. However, although resistant, mice are known to be chronically infected by leptospires. Interestingly, the leptospiral LPS has low endotoxicity in mouse cells and is an agonist of TLR2, the sensor for bacterial lipoproteins. Here, we investigated the signaling properties of the leptospiral LPS in mouse macrophages. Using confocal microscopy and flow cytometry, we showed that the LPS of L. interrogans did not induce internalization of mTLR4, unlike the LPS of Escherichia coli. Consequently, the LPS failed to induce the production of the TRIF-dependent nitric oxide and RANTES, both important antimicrobial responses. Using shorter LPS and LPS devoid of TLR2 activity, we further found this mTLR4-TRIF escape to be dependent on both the co-purifying lipoproteins and the full-length O antigen. Furthermore, our data suggest that the O antigen could alter the binding of the leptospiral LPS to the co-receptor CD14 that is essential for TLR4-TRIF activation. Overall, we describe here a novel leptospiral immune escape mechanism from mouse macrophages and hypothesize that the LPS altered signaling could contribute to the stealthiness and chronicity of the leptospires in mice.

The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.

The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. This Perspective discusses how the function of the Toll-like receptors may relate to these processes in the context of carcinogenesis. Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.

Key Points Toxoplasma gondii is a protozoan parasite that infects more than 1 billion people in the world. In addition to humans, T. gondii can infect all mammals and birds. Mice are a natural host for T. gondii and are a thoroughly studied animal model for T. gondii infection. In mice, Toll-like receptor 11 (TLR11) is the principal innate immune sensor for T. gondii . TLR11 recognizes the unconventional actin-binding protein profilin, which is essential for parasite invasion into host cells. In humans, TLR11 is a nonfunctional pseudogene. Consequently, the mechanisms through which the human immune system recognizes T. gondii are not well understood. Additional TLRs, in particular TLR2, TLR7 and TLR9, as well as the NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome are all possible candidates for innate immune sensors that could be involved in human defence against T. gondii . In a mouse model, activation of TLR11 and myeloid differentiation primary-response protein 88 (MYD88) in dendritic cells leads to the induction of interleukin-12 (IL-12) expression and the activation of interferon-γ (IFNγ) production by natural killer (NK) cells. In addition, both CD4 + T cell-derived and CD8 + T cell-derived IFNγ is essential for host resistance to the parasite. An emerging source of IFNγ that does not require TLR-mediated parasite recognition is the neutrophil. IFNγ mediates host protection via multiple mechanisms including induction of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). IFNγ also triggers the induction of the antimicrobial molecules nitric oxide and reactive oxygen species and is responsible for changes in host metabolism that restrict T. gondii replication. Much research into Toxoplasma gondii infection has concentrated on adaptive T helper 1 cell responses. More recently, scientists have focused on the innate immune pathways that enable control of T. gondii infection. This Review compares the innate immune response to T. gondii in mice and humans, with a particular focus on Toll-like receptor-dependent pathways. Toxoplasma gondii is a protozoan parasite of global importance. In the laboratory setting, T. gondii is frequently used as a model pathogen to study mechanisms of T helper 1 (T H 1) cell-mediated immunity to intracellular infections. However, recent discoveries have shown that innate type 1 immune responses that involve interferon-γ (IFNγ)-producing natural killer (NK) cells and neutrophils, rather than IFNγ-producing T cells, predetermine host resistance to T. gondii . This Review summarizes the Toll-like receptor (TLR)-dependent mechanisms that are responsible for parasite recognition and for the induction of IFNγ production by NK cells, as well as the emerging data about the TLR-independent mechanisms that lead to the IFNγ-mediated elimination of T. gondii .

Toll-like receptor 4 (TLR4) induces two distinct signaling pathways controlled by the TIRAP-MyD88 and TRAM-TRIF pairs of adaptor proteins, which elicit the production of proinflammatory cytokines and type I interferons, respectively. How TLR4 coordinates the activation of these two pathways is unknown. Here we show that TLR4 activated these two signaling pathways sequentially in a process organized around endocytosis of the TLR4 complex. We propose that TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed and activates TRAM-TRIF signaling from early endosomes. Our data emphasize a unifying theme in innate immune recognition whereby all type I interferon–inducing receptors signal from an intracellular location.

Infectious and autoimmune diseases are associated with anemia and thrombocytopenia. A severe form of inflammatory cytopenia called macrophage activation syndrome (MAS) may occur during rheumatological disorders and viral infections. Akilesh et al. show that monocyte recognition of self- or pathogen-derived nucleic acids via Toll-like receptors 7 and 9 (TLR7 and TLR9) drives MAS-like disease in mice. TLR7 or TLR9 signaling in monocytes causes these cells to differentiate into inflammatory hematophagocytes (iHPCs), which are similar to but distinct from red pulp macrophages. Preventing iHPC differentiation by depleting monocytes relieves MAS-like symptoms. When mice were subjected to a model of malarial anemia, MyD88- and endosomal TLR-dependent iHPC differentiation also occurred. Thus, iHPCs may play a role in both MAS-driven and malarial anemia, as well as thrombocytopenia. Science , this issue p. eaao5213 Immune receptor signaling underlies the process whereby inflammatory hemophagocytes drive anemia and thrombocytopenia. Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)–driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6C hi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)–like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.

Activin A is a member of the transforming growth factor-β superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1β, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-μg dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases.

Heart failure (HF) represents a major public health burden. Inflammation has been shown to be a critical factor in the progression of HF, regardless of the aetiology. Disappointingly, the majority of clinical trials targeting aspects of inflammation in patients with HF have been largely negative. Many clinical researches demonstrate that danshen has a good efficacy on HF, and however, whether danshen exerts anti‐inflammatory effects against HF remains unclear. In our study, the employment of a water extracted and alcohol precipitated of danshen extract attenuated cardiac dysfunction and inflammation response in acute myocardial infarction‐induced HF rats. Transcriptome technique and validation results revealed that TLR4 signalling pathway was involved in the anti‐inflammation effects of danshen. In vitro, danshen reduced the release of inflammatory mediators in LPS‐stimulated RAW264.7 macrophage cells. Besides, the LPS‐stimulated macrophage conditioned media was applied to induce cardiac H9C2 cells injury, which could be attenuated by danshen. Furtherly, knock‐down and overexpression of TLR4 were utilized to confirm that danshen ameliorated inflammatory injury via MyD88‐dependent TLR4‐TRAF6‐NF‐κB signalling pathway in cardiomyocytes. Furthermore, by utilizing co‐immunoprecipitation, danshen was proved to suppress MD2/TLR4 complex formation and MyD88 recruitment. In conclusion, our results demonstrated that danshen ameliorates inflammatory injury by controlling MD2/TLR4‐MyD88 complex formation and TLR4‐TRAF6‐NF‐κB signalling pathway in acute myocardial infarction‐induced HF.

Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3'-methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88⁻/⁻ mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNF-deficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model.