Alarmins

RATIONALE: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro . OBJECTIVES: Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma...

Environmental airborne antigens are central to the development of allergic asthma, but the cellular processes that trigger disease remain incompletely understood. In this report, Schmitt et al. (https://doi.org/10.1084/jem.20231236) identify TNF-like protein 1A (TL1A) as an epithelial alarmin constitutively expressed by a subset of lung epithelial cells, which is released in response to airborne microbial challenge and synergizes with IL-33 to drive allergic disease.

Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9...

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function...

Neurons have the unique capacity to adapt output in response to changes in their environment. Within seconds, sensory nerve endings can become hypersensitive to stimuli in response to potentially damaging events. The underlying behavioral response is well studied, but several of the key signaling molecules that mediate sensory hypersensitivity remain unknown. We previously discovered that peripheral voltage-gated Ca V 2.2 channels in nerve endings in skin are essential for the rapid, transient increase in sensitivity to heat, but not to mechanical stimuli, that accompanies intradermal capsaicin...

INTRODUCTION: The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis...

PURPOSE OF REVIEW: This review aims to explore role of emerging biologics, including ligelizumab, UB-221, dupilumab, and antialarmins, in food allergy management. With a focus on recent developments, we evaluate their promise in mitigating adverse events during oral immunotherapy (OIT), reducing allergic reactions, and addressing the limitations of current therapeutic options. RECENT FINDINGS: Antiimmunoglobulin E mAbs, exemplified by omalizumab, demonstrate efficacy in desensitization and safety improvement during multiallergen OIT...

LTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendritic cell (DC) maturation in the induction of antigen-specific immunity, we investigated the effect of LTX-315 treatment on the maturation of tumor-infiltrating DCs (TiDCs) and the generation of anti-melanoma immunity...

Despite promising advancements in oral immunotherapy for food allergies, medical implementation faces limitations. Non-specific treatment options based on inhibiting the type 2 inflammatory pathway, including monoclonal antibodies, are under investigation. TNX-901 and omalizumab have demonstrated increased reaction thresholds, reducing adverse events in peanut-allergic patients. Dupilumab, blocking the IL-4 receptor, shows positive results in both food allergies and eosinophilic esophagitis. Antibodies against alarmins and anti-IL-5, such as etokimab and mepolizumab, have proven efficacy in preclinical studies and clinical trials...

Group 2 Innate Lymphoid Cells (ILC2s) are innate lymphocytes involved in type 2 immunity. ILC2s are abundant at the barrier tissues and upon allergen exposure, respond to epithelial-derived alarmins by producing type 2 cytokines (e.g., IL-5 and IL-13). Upon activation, some of these activated ILC2s acquire immunological memory and can mount enhanced responses upon further allergen encounters. Here, we review recent findings of the cellular and molecular mechanisms underlying immune memory in ILC2s both in mice and humans and discuss the implications of memory ILC2s in the context of allergic diseases...

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation...

Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not...

BACKGROUND: Wildfires are a global concern due to their wide-ranging environmental, economic, and public health impacts. Climate change contributes to an increase in the frequency and intensity of wildfires making smoke exposure a more significant and recurring health concern for individuals with airway diseases. Some of the most prominent effects of wildfire smoke exposure are asthma exacerbations and allergic airway sensitization. Likely due to the delayed recognition of its health impacts in comparison with cigarette smoke and industrial or traffic-related air pollution, research on the composition, the mechanisms of toxicity, and the cellular/molecular pathways involved is poor or non-existent...

Stroke, trauma, and neurodegenerative disorders cause loss of neurites (axons and dendrites) in addition to neuronal death. Neurite loss may result directly from a primary insult, secondary to parental neuron death, or secondary to a post-injury inflammatory response. Here, we use lipopolysaccharide and the alarmin S100β to selectively evaluate neurite loss caused by the inflammatory response. Activation of microglia and infiltrating macrophages by these stimuli causes neurite loss that far exceeds neuronal death, both in vitro and in vivo...

Rosacea is a chronic inflammatory skin disorder characterized by immune response-dependent erythema and pustules. S100 calcium binding protein A9 (S100A9), a pro-inflammatory alarmin, has been associated with various inflammation-related diseases. However, the specific role of S100A9 in rosacea remains unexplored. Therefore, our objective was to unravel the role of S100A9 in the pathogenesis of rosacea and its underlying molecular mechanisms. Here, we show that expression levels of S100A9 were elevated in both the lesions and serum of PPR patients, as well as in lesions of the LL37-induced rosacea-like mouse model...

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OBJECTIVE: Calprotectin (CLP), S100A6, and High Mobility Group Nucleosome-Binding Protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to inve stigate the relationship of serum CLP, S100A6, and HMGN1 levels with clinical and laboratory findings in Multiple Myeloma (MM) patients and their role in the pathogenesis of MM. MATERIALS AND METHODS: We measured serum CLP, S100A6, and HMGN1 levels in 55 newly diagnosed patients and 32 healthy controls (HC)...

Lymphocytes spanning the entire innate-adaptive spectrum can stably reside in tissues and constitute an integral component of the local defense network against immunological challenges. In tight interactions with the epithelium and endothelium, tissue-resident lymphocytes sense antigens and alarmins elicited by infectious microbes and abiotic stresses at barrier sites and mount effector responses to restore tissue homeostasis. Of note, such a host cell-directed immune defense system has been recently demonstrated to surveil epithelial cell transformation and carcinoma development, as well as cancer cell metastasis, at selected distant organs and thus represents a primordial cancer immune defense module...

Heterogeneity characterises inflammatory diseases and different phenotypes and endotypes have been identified. Both innate and adaptive immunity contribute to the immunopathological mechanism of these diseases and barrier damage plays a prominent role triggering type 2 inflammation through the alarmins system, such as anti-Thymic Stromal Lymphopoietin (TSLP). Treatment with anti-TSLP monoclonal antibodies showed efficacy in severe asthma and clinical trials for other eosinophilic diseases are ongoing. The aim of this perspective review is to analyse current advances and future applications of TSLP inhibition to control barrier damage...

Sulfurous thermal waters (STWs) are used as a complementary treatment for allergic rhinitis. However, there is scant data on the effects of STW on nasal epithelial cells, and in vitro models are warranted. The main aim of this study was to evaluate the dose and time effects of exposure to 3D nasal inserts (MucilAirTM -HF allergic rhinitis model) with STW or isotonic sodium chloride solution (ISCS) aerosols. Transepithelial electrical resistance (TEER) and histology were assessed before and after nebulizations...