Innate Immune Dysfunction in Trauma Patients

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses.

Studies that bridge innate immunity and various diseases are making rapid advances. Macrophages and dendritic cells play a leading role in innate immunity, using pattern recognition receptors (PRRs) to sense both pathogen invasion and danger signals. Among these PRRs, the Toll-like receptors (TLRs) play a central role in the immune response by recognizing not only pathogen-associated molecular patterns from bacteria and viruses but also damage-associated molecular patterns from dying or injured cells. These TLR family molecules facilitate not only the elimination of pathogens but also the development of various disorders, including arteriosclerosis, cancer, and metabolic syndrome. TLRs activate signaling pathways that result in the production of cytokines, chemokines, and various inducible molecules associated with the immune response. Although most components of the innate immune signaling pathways, such as the TLR family and its downstream signaling, have been identified, the physiological roles of many TLR signal-inducible proteins remain unclear. Recent studies have shown that some TLR-inducible proteins are critical in the immune response and the development of various disorders. In this review, we focus on the TLR signaling pathways and the roles of some TLR-inducible proteins.

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

Autoimmunity--promoting and stabilizing innate immunity 'UNWUCHT'.

IFN-α Enhances Poly-IC Responses in Human Keratinocytes by Inducing Expression of Cytosolic Innate RNA Receptors: Relevance for Psoriasis

Aprominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. The legend describes striking “onion skin” changes of a renal arteriole. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed. This lack of attention to inflammatory cells is, however, not surprising. Although many experimental studies have implicated inflammation in hypertension, these have largely been performed in experimental animals; there is no proof that inflammation contributes to human hypertension. In fact, some anti-inflammatory or immune-suppressing drugs (eg, nonsteroidal anti-inflammatory drugs and cyclosporine) paradoxically cause hypertension in humans, likely via off-target effects. Often the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein or the presence of macrophages in a tissue. Most clinicians and investigators find this vague and difficult to understand. Even more puzzling is that many studies now implicate the adaptive immune response, and in particular, lymphocytes, in hypertension and vascular disease. Traditionally, bacterial, viral, or tumor antigens activate this arm of immune defense. As such, it has been hard to imagine how adaptive immunity could be involved in a disease such as hypertension. In this article, we will attempt to address some of these puzzling questions. We will briefly review components of the innate and adaptive immune response, discuss data from many groups, including our own, that suggest that common forms of hypertension are immune mediated, and provide a working hypothesis of how signals from the central nervous system trigger an immune response that causes hypertension. ### General Concepts Regarding Inflammation and Immunity #### Innate Immunity The first line of defense against pathogens is the innate immune response. Important components of this system include epithelial …

Innate immunity and HCV

Innate immunity and cardiomyocytes in ischemic heart disease

EDITORIAL article Front. Immunol., 16 September 2015Sec. Cancer Immunity and Immunotherapy Volume 6 - 2015 | https://doi.org/10.3389/fimmu.2015.00481

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expressions of pattern recognition receptors (PRRs) also cause diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not yet been revealed. Based on TLR4-deficient (TLR4-/-) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type 2 dendritic cells (CD8α- CD11b+ cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of follicular helper T (Tfh) cells promotes the proliferation of germinal center (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4-deficient (TLR4-/-) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG compared to that occurred in wild-type (WT) mice. As a consequence, TLR4-/- mice exhibited higher mortality than that of WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α+ CD11b-), a subset of cDCs known to induce CD4+ T-cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

The immune response to microbial pathogens relies on both innate and adaptive components.1 The innate or immediate response is mediated in large measure by leukocytes of the blood, such as neutrophils (PMNs) and macrophages, cells that phagocytose and kill the pathogens and that concurrently coordinate additional host responses by synthesis of a wide range of inflammatory mediators and cytokines.2 A primary challenge to the innate immune system is the ability to discriminate among a large number of potential pathogens from self, with the use of a restricted number of receptors. This discrimination is achieved by the evolution of a variety of receptors that recognize conserved motifs on pathogens called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs), perhaps the best-characterized class of pattern-recognition receptors (PRRs)3,4 in mammalian species, play an important role in the recognition of components of pathogens and activation of innate immunity, which then leads to development of adaptive immune responses.5 In the eye, as in other parts of the body, the early response against invading pathogens is provided by innate immunity. It is now well established that the recognition of pathogens by the innate defense system is mediated through germ line–encoded PRRs,6,7 most notably, TLRs.4,8,9 A growing number of studies have shown that TLRs are expressed by a variety of tissues and cells of the eye and play an important role in ocular protection and defense against microbial infection.10–20 The TLR family of receptors links the extracellular compartment where contact and recognition of PAMPs occur and the intra-cellular compartment, where signaling cascades leading to cellular responses are initiated. Their extracellular domain contains leucine-rich repeats (LRRs), whereas the cytoplasmic domain shows a striking homology with that of the interleukin-1 receptor (IL-1R) and is referred to as the Toll/IL-1R (TIR) domain. The Toll/IL-1Rs play a critical role in host defense and inflammation.21 Ten TLRs have been identified in humans, whereas 13 can be found in the mouse genome.22 Individual TLRs recognize distinct microbial components or PAMPs.4 Recognition of PAMPs by TLRs induces the production of signals responsible for the activation of genes that are essential for an effective host defense, especially proinflammatory cytokine genes.8,23 One of the first mammalian receptors identified was TLR4.24,25 Figure 1 shows TLRs, their known ligands (or PAMPs), downstream signaling pathways, and their role in mediating innate responses in cells. TLR4 is the extensively studied PRR and has been shown to be capable of sensing lipopolysaccharide (LPS) and initiating responses.26 TLR2 has been shown to recognize a broad range of microbial components including bacterial and mycoplasma lipoproteins and yeast carbohydrates.27 TLR3 is necessary for the response to double-stranded RNA (dsRNA),28 TLR5 for the response to bacterial flagellin,29 TLR7 and -8 for the response to single-stranded RNA (ssRNA),30,31 and TLR9 for the response to the unmethylated CpG motifs found in both bacterial and viral DNA.32,33 There are no specific ligands identified for TLR1 and -6; however, they are known to form heterodimers with TLR2, dictating the specificity of TLR2 ligand recognition.34 Little is known about TLR10.35 Figure 1 TLR signaling and the role of epithelium in corneal innate defense. When cells are exposed to pathogens, TLRs such as TLR2, -4, and -5 at the cell surface recognize PAMPs such as lipoproteins, LPS, and flagellin, respectively. In contrast, nucleic acids ...

Toll-like receptors(TLRs)are the bona fide pattern recognition receptors(PRRs)that ale capable to recognize the pathogen associated molecular patterns(PAMPs)of infectious agents to activate innate immune cells and further modulate adaptive immune system.Recent discoveries indicate that TLRs also play an important role in the initiation and progression of cancer.Moreover.the agonists and/or antagonists of TLRs have been used for anti-cancer immunotherapy as immunoadjuvants or cyto-toxic drugs.Thus,TLRs are not only involved in immune responses to prevent exogenous pathogen infection but also play an im-portant role in cancer immunity,and can served as an important target for cancer immunotherapy.In this re-view,we will discuss the current progress about the role of TLRs in cancer development and cancer immuno-therapy. Key words: Toll-like receptor; Cancer; Innate immunity; TLR signaling; NF-kB

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder marked by autoantibody-mediated dysfunction at the neuromuscular junction, resulting in fluctuating muscle weakness. The pathogenesis of MG involves a complex interplay between genetic predisposition, environmental factors, and immune system dysregulation. Among these, the innate immune system, particularly Toll-like receptors (TLRs), has emerged as a critical player in disease progression by influencing both innate and adaptive immunity. TLRs are a family of pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering immune responses. Dysregulation of TLRs expression and signaling in MG has been implicated in chronic inflammation, breakdown of immune tolerance, and activation of autoreactive T and B cells. Overexpression of specific TLRs, such as TLR4 and TLR9, has been reported in MG patients, particularly in thymic tissues and peripheral immune cells, correlating with increased pro-inflammatory cytokine production and autoantibody generation. These aberrant responses contribute to the autoimmune cascade that underlies MG. Emerging evidence highlights the therapeutic potential of targeting TLRs pathways in MG. Strategies include using TLRs antagonists, modulating downstream signaling pathways, and leveraging epigenetic regulators to normalize TLRs activity. This review examines the role of TLRs in MG by exploring their expression profiles, their involvement in inflammatory signaling pathways, their impact on the adaptive immune system, and their potential as therapeutic targets. A better understanding of the role of TLRs in MG pathogenesis could open new avenues for modulating immune responses and precision therapies targeting the innate immune system.

Innate immunity is present in all animals. In this review, we explore the main conserved mechanisms of recognition and innate immune responses among animals. In this sense, we discuss the receptors, critical for binding to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs); the downstream signaling proteins; and transcription factors that govern immune responses. We also highlight conserved inflammatory mediators that are induced after the recognition of DAMPs and PAMPs. At last, we discuss the mechanisms that are involved in the regulation and/or generation of reactive oxygen species (ROS), influencing immune responses, like heme-oxygenases (HOs).