Allergens abrogate antiinflammatory DNA effects and unmask macrophage-driven neutrophilic asthma via ILC2/STING/TNF-α signaling.

The mechanisms of neutrophilic and mixed neutrophilic-eosinophilic asthma are poorly understood. We found that extracellular DNA and nucleosomes (Nucs) were elevated in the airways of patients with neutrophilic-eosinophilic asthma and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma had more DNA sensor-positive cells.

NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown.

Objective: NFκB1 is preferentially expressed at a high level in ILC2s.

Isolation and Characterization of Conventional and Non-conventional Type 2 Innate Lymphoid Cells (ILC2s) from Human Peripheral Blood Mononuclear Cells (PBMCs).

Innate lymphoid cells (ILCs) are a relatively new family of lymphoid cells that lack lineage cell surface markers but produce various effector cytokines. Based on phenotype and function, the group 2 ILCs (ILC2s) mirror the features of the adaptive CD4 Th2 cell subset. In humans, they are traditionally characterized as the LinIL7RαCRΤΗ2CD161 cell population that produces type 2 cytokines - IL-5 and IL-13.

The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma.

Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma.

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines.

Optimal identification of human conventional and nonconventional (CRTH2IL7Rα) ILC2s using additional surface markers.

Background: Human type 2 innate lymphoid cells (ILC2s) are identified by coupled detection of CRTH2 and IL7Rα on lineage negative (Lin) cells. Type 2 cytokine production by CRTH2IL7Rα innate lymphoid cells (ILCs) is unknown.

Objective: We sought to identify CRTH2IL7Rα type 2 cytokine-producing ILCs and their disease relevance.

Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9 and IL-13 type 2 innate lymphoid cell subpopulations.

Background: IL-33 plays an important role in the development of experimental asthma.

Objective: We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model.

Methods: We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice.

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin.

Background: Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown.

Objective: We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction.

A Disease-associated Mutant of NLRC4 Shows Enhanced Interaction with SUG1 Leading to Constitutive FADD-dependent Caspase-8 Activation and Cell Death.

Nod-like receptor family card containing 4 (NLRC4)/Ipaf is involved in recognition of pathogen-associated molecular patterns leading to caspase-1 activation and cytokine release, which mediate protective innate immune response. Point mutations in NLRC4 cause autoinflammatory syndromes. Although all the mutations result in constitutive caspase-1 activation, their phenotypic presentations are different, implying that these mutations cause different alterations in properties of NLRC4.

The specific, reversible JNK inhibitor SP600125 improves survivability and attenuates neuronal cell death in experimental cerebral malaria (ECM).

Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum in humans and major cause of death. SP600125 is a specific, small molecule inhibitor of JNK that prevents the phosphorylation of c-Jun and blocks the expression of proinflammatory cytokines and attenuates neuronal apoptosis in several neurodegenerative disorders. We evaluated the effect of SP600125 treatment on the survival of Plasmodium berghei ANKA (PbA)-infected C57BL/6J mice.

Endoplasmic reticulum stress and neurodegeneration in experimental cerebral malaria.

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA (PbA) infection in mice results in neuronal cell death. However, the precise mechanisms leading to neuronal cell death in ECM have not been fully elucidated. In the present study, we report the presence of endoplasmic reticulum (ER) stress markers and activation of the unfolded protein response (UPR) in the brain during the pathogenesis of ECM.

c-Jun N terminal kinases (JNK) are activated in the brain during the pathology of experimental cerebral malaria.

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA (PbA) infection in C57BL/6J mice manifests cell death in the brain. However, the precise molecular and biochemical mechanisms regulating cell death during ECM remains unknown. In this study we have examined, the role of a stress activated protein kinase called c-Jun N terminal kinase during the pathology of ECM.