Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: The Role of the Complement and Innate Immune System.

Specific inflammatory pathways are important in the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Understanding the specific pathways of inflammation may be critical for finding new treatments. Evidence is accumulating that innate inflammatory cells and proteins play a more important role than cells of the adaptive inflammatory system. In this work, we review the evidence from clinical and preclinical data regarding which cells of the immune system play a role in DCI with particular emphasis on the bone-marrow-derived cells monocytes and neutrophils and the brain parenchymal microglia. In addition, we will review the evidence that complement proteins, a non-cellular part of the innate immune system, play a role in the development of DCI.

Erratum: Single cell analysis of short-term dry eye induced changes in cornea immune cell populations.

[This corrects the article DOI: 10.3389/fmed.2024.1362336.].

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations.

Background: Dry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry eye alters the percentages and transcriptional profiles of immune cell populations in the cornea. Methods: Desiccating stress (DS) induced dry eye was created by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Expression profiling of corneal immune cells was performed by single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories and cell fate were modeled through RNA velocity analysis. Confocal microscopy was used to immunodetect corneal immune cells. Irritation response to topical neurostimulants was assessed. Results: Twelve corneal immune cell populations based on their transcriptional profiles were identified at baseline and consist of monocytes, resident (rMP) and MMP12/13 high macrophages, dendritic cells (cDC2), neutrophils, mast cells, pre T/B cells, and innate (γDT, ILC2, NK) and conventional T and B lymphocytes. T cells and resident macrophages (rMP) were the largest populations in the normal cornea comprising 18.6 and 18.2 percent, respectively. rMP increased to 55.2% of cells after 5 days of DS. Significant changes in expression of 1,365 genes (adj p < 0.0001) were noted in rMP with increases in cytokines and chemokines (Tnf, Cxcl1, Ccl12, Il1rn), inflammatory markers (Vcam, Adam17, Junb), the TAM receptor (Mertk), and decreases in complement and MHCII genes. A differentiation trajectory from monocytes to terminal state rMP was found. Phagocytosis, C-type lectin receptor signaling, NF-kappa B signaling and Toll-like receptor signaling were among the pathways with enhanced activity in these cells. The percentage of MRC1+ rMPs increased in the cornea and they were observed in the basal epithelium adjacent to epithelial nerve plexus. Concentration of the chemokine CXCL1 increased in the cornea and it heightened irritation/pain responses to topically applied hypertonic saline. Conclusion: These findings indicate that DS recruits monocytes that differentiate to macrophages with increased expression of inflammation associated genes. The proximity of these macrophages to cornea nerves and their expression of neurosensitizers suggests they contribute to the corneal sensorineural changes in dry eye.

NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1.

Innate inflammation is crucial for ischemic stroke development. NLRP6, a nucleotide-binding and oligomerization domain-like receptors (NLRs) family member, regulates innate inflammation. Whether NLRP6 regulates neurological damage and neuroinflammation during ischemic stroke remains unclear. We report that NLRP6 is abundantly expressed in microglia and significantly upregulated in the ischemic brain. The brain injury severity was alleviated in NLRP6-deficient mice after ischemic stroke, as evidenced by reduced cerebral infarct volume, decreased neurological deficit scores, improved histopathological morphological changes, ameliorated neuronal denaturation, and relief of sensorimotor dysfunction. In the co-culture OGD/R model, NLRP6 deficiency prevented neuronal death and attenuated microglial cell injury. NLRP6 deficiency blocked several NLRs inflammasomes' activation and abrogated inflammasome-related cytokine production by decreasing the expression of the common effector pro-caspase-1. NLRP6 deficiency reduced pro-caspase-1's protein level by inducing proteasomal degradation. These findings confirm the neuroprotective role of NLRP6 deficiency in ischemic stroke and its underlying regulation mechanism in neuroinflammation and provide a potential therapeutic target for ischemic stroke.

Meloxicam treatment disrupts the regional structure of innate inflammation sites by targeting the pro-inflammatory effects of prostanoids.

BACKGROUND AND PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed drugs in the world due to their analgesic, antipyretic and anti-inflammatory effects. However, NSAIDs inhibit prostanoid synthesis, interfering with their pro-inflammatory and anti-inflammatory functions and potentially prolonging acute inflammation. EXPERIMENTAL APPROACH: We used high-content immunohistochemistry to define the impact of meloxicam treatment on spatially separated pro-inflammatory and anti-inflammatory processes during innate inflammation in mice induced by zymosan. This allowed us to determine the effect of meloxicam treatment on the organization of pro-inflammatory and anti-inflammatory microenvironments, thereby identifying relevant changes in immune cell localization, recruitment and activation. KEY RESULTS: Meloxicam treatment reduced zymosan-induced thermal hypersensitivity at early time points but delayed its resolution. High-content immunohistochemistry revealed that the pro-inflammatory area was smaller after treatment, diminishing neutrophil recruitment, M1-like macrophage polarization, and especially phagocytosis by neutrophils and macrophages. The polarization of macrophages towards the M2-like anti-inflammatory phenotype was unaffected, and the number of anti-inflammatory eosinophils actually increased. CONCLUSION AND IMPLICATIONS: High-content immunohistochemistry was able to identify relevant meloxicam-mediated effects on inflammatory processes based on alterations in the regional structure of inflammation sites. Meloxicam delayed the clearance of pathogens by inhibiting pro-inflammatory processes, causing prolonged inflammation. Our data suggest that the prescription of NSAIDs as a treatment during an acute pathogen-driven inflammation should be reconsidered in patients with compromised immune systems.

Corrigendum: MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

[This corrects the article DOI: 10.3389/fimmu.2023.1193179.].

MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-ß, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1ß and TNF. Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

Immune mechanisms in vulvodynia: key roles for mast cells and fibroblasts.

Vulvodynia is a debilitating condition characterized by painful sensitivity to touch and pressure in the vestibular tissue surrounding the vaginal opening. It is often a "diagnosis of exclusion" of idiopathic pain made in the absence of visible inflammation or injury. However, the association between increased vulvodynia risk and a history of yeast infections and skin allergies has led researchers to explore whether immune mechanisms of dysregulated inflammation might underlie the pathophysiology of this chronic pain condition. Here we synthesize epidemiological investigations, clinical biopsies and primary cell culture studies, and mechanistic insights from several pre-clinical models of vulvar pain. Taken together, these findings suggest that altered inflammatory responses of tissue fibroblasts, and other immune changes in the genital tissues, potentially driven by the accumulation of mast cells may be key to the development of chronic vulvar pain. The association of increased numbers and function of mast cells with a wide variety of chronic pain conditions lends credence to their involvement in vulvodynia pathology and underscores their potential as an immune biomarker for chronic pain. Alongside mast cells, neutrophils, macrophages, and numerous inflammatory cytokines and mediators are associated with chronic pain suggesting immune-targeted approaches including the therapeutic administration of endogenous anti-inflammatory compounds could provide much needed new ways to treat, manage, and control the growing global pandemic of chronic pain.

'Hippocampal innate inflammatory gliosis only' in pharmacoresistant temporal lobe epilepsy.

Drug-resistant mesial-temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as 'gliosis only' with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that 'gliosis only' represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. On the basis of their neuropathological exam, patients with hippocampus sclerosis and 'gliosis only' were characterized and compared within the whole cohort and within a subset of matched pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. 'Gliosis only' revealed demographics, clinical and neuropsychological outcome fundamentally different from hippocampus sclerosis. 'Gliosis only' patients had a significantly later seizure onset (16.3 versus 12.2 years, P = 0.005) and worse neuropsychological outcome after surgery compared to patients with hippocampus sclerosis. Epilepsy was less amendable by surgery in 'gliosis only' patients, resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% versus 68%, P = 0.0001, odds ratio = 2.8, confidence interval 1.7-4.7). This finding remained significant after multivariate and matched-pairs analysis. The 'gliosis only' group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in hippocampus sclerosis. RNA-sequencing of gliosis only patients deciphered a distinct transcriptional programme that resembles an innate inflammatory response of reactive astrocytes. Our data indicate a new temporal lobe epilepsy syndrome for which we suggest the term 'Innate inflammatory gliosis only'. 'Innate inflammatory gliosis only' is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, 'innate inflammatory gliosis only' patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients; surgical treatment of this subgroup should be considered with great precaution. 'Innate inflammatory gliosis only' requires innovative pharmacotreatment strategies.

Eosinophil-derived IL-4 is necessary to establish the inflammatory structure in innate inflammation.

Pathogen-induced inflammation comprises pro- and anti-inflammatory processes, which ensure pathogen removal and containment of the proinflammatory activities. Here, we aimed to identify the development of inflammatory microenvironments and their maintenance throughout the course of a toll-like receptor 2-mediated paw inflammation. Within 24 h after pathogen-injection, the immune cells were organized in three zones, which comprised a pathogen-containing "core-region", a bordering proinflammatory (PI)-region and an outer anti-inflammatory (AI)-region. Eosinophils were present in all three inflammatory regions and adapted their cytokine profile according to their localization. Eosinophil depletion reduced IL-4 levels and increased edema formation as well as mechanical and thermal hypersensitivities during resolution of inflammation. Also, in the absence of eosinophils PI- and AI-regions could not be determined anymore, neutrophil numbers increased, and efferocytosis as well as M2-macrophage polarization were reduced. IL-4 administration restored in eosinophil-depleted mice PI- and AI-regions, normalized neutrophil numbers, efferocytosis, M2-macrophage polarization as well as resolution of zymosan-induced hypersensitivity. In conclusion, IL-4-expressing eosinophils support the resolution of inflammation by enabling the development of an anti-inflammatory framework, which encloses proinflammatory regions.

cGAS/STING and innate brain inflammation following acute high-fat feeding.

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer's disease and Alzheimer's disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.

Non-immune and immune functions of interleukin-36γ suppress epithelial repair at the ocular surface.

Regulation of innate inflammation is critical for maintaining tissue homeostasis and barrier function, especially in those interfacing the external environments such as the skin and cornea. Expression of pro-inflammatory cytokines by injured tissues has been shown to exacerbate the inflammatory cascade, causing tissue damage. Interleukin 36, a subfamily of the IL-1 superfamily, consists of three pro-inflammatory agonists-IL36α, IL36ß, and IL36γ and an IL36 receptor antagonist (IL36Ra). The current investigation, for the first time, reports that IL36γ is the primary agonist expressed by the corneal epithelium, which is significantly upregulated following corneal injury. The function of IL36γ on non-immune cells, in addition to innate inflammatory cells, in regulating tissue homeostasis has not been well investigated. Using a loss-of-function approach via neutralizing antibody treatment, our data demonstrate that blocking endogenously expressed IL36γ in epithelial cells promotes rapid re-epithelialization in in vitro wound closure assay. Finally, by utilizing a naturally occurring antagonist IL36Ra in a well-established murine model of ocular injury, our study demonstrates that inhibition of IL36γ accelerates epithelial regeneration and suppresses tissue inflammation. Given rapid wound healing is critical for re-establishing normal tissue structure and function, our investigation on the function of IL36γ provides evidence for the development of novel IL36γ-targeting strategies to promote tissue repair.

Quantification and role of innate lymphoid cell subsets in Chronic Obstructive Pulmonary Disease.

OBJECTIVES: Innate lymphoid cells (ILCs) secrete cytokines, such as IFN-γ, IL-13 and IL-17, which are linked to chronic obstructive pulmonary disease (COPD). Here, we investigated the role of pulmonary ILCs in COPD pathogenesis. METHODS: Lung ILC subsets in COPD and control subjects were quantified using flow cytometry and associated with clinical parameters. Tissue localisation of ILC and T-cell subsets was determined by immunohistochemistry. Mice were exposed to air or cigarette smoke (CS) for 1, 4 or 24 weeks to investigate whether pulmonary ILC numbers and activation are altered and whether they contribute to CS-induced innate inflammatory responses. RESULTS: Quantification of lung ILC subsets demonstrated that ILC1 frequency in the total ILC population was elevated in COPD and was associated with smoking and severity of respiratory symptoms (COPD Assessment Test [CAT] score). All three ILC subsets localised near lymphoid aggregates in COPD. In the COPD mouse model, CS exposure in C57BL/6J mice increased ILC numbers at all time points, with relative increases in ILC1 in bronchoalveolar lavage (BAL) fluid. Importantly, CS exposure induced increases in neutrophils, monocytes and dendritic cells that remained elevated in Rag2/Il2rg-deficient mice that lack adaptive immune cells and ILCs. However, CS-induced CXCL1, IL-6, TNF-α and IFN-γ levels were reduced by ILC deficiency. CONCLUSION: The ILC1 subset is increased in COPD patients and correlates with smoking and severity of respiratory symptoms. ILCs also increase upon CS exposure in C57BL/6J mice. In the absence of adaptive immunity, ILCs contribute to CS-induced pro-inflammatory mediator release, but are redundant in CS-induced innate inflammation.

Microbiota-Derived Metabolites, Indole-3-aldehyde and Indole-3-acetic Acid, Differentially Modulate Innate Cytokines and Stromal Remodeling Processes Associated with Autoimmune Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1ß and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes.

Role of innate inflammation in traumatic brain injury.

Traumatic brain injury is one of the leading causes of morbidity and mortality throughout the world. Its increasing incidence, in addition to its fundamental role in the development of neurodegenerative disease, proves especially concerning. Despite extensive preclinical and clinical studies, researchers have yet to identify a safe and effective neuroprotective strategy. Following brain trauma, secondary injury from molecular, metabolic, and cellular changes causes progressive cerebral tissue damage. Chronic neuroinflammation following traumatic brain injuries is a key player in the development of secondary injury. Targeting this phenomenon for development of effective neuroprotective therapies holds promise. This strategy warrants a concrete understanding of complex neuroinflammatory mechanisms. In this review, we discuss pathophysiological mechanisms such as the innate immune response, glial activation, blood-brain barrier disruption, activation of immune mediators, as well as biological markers of traumatic brain injury. We then review existing and emerging pharmacological therapies that target neuroinflammation to improve functional outcome.

The Hexosamine Biosynthetic Pathway Links Innate Inflammation With Epithelial-Mesenchymal Plasticity in Airway Remodeling.

Disruption of the lower airway epithelial barrier plays a major role in the initiation and progression of chronic lung disease. Here, repetitive environmental insults produced by viral and allergens triggers metabolic adaptations, epithelial-mesenchymal plasticity (EMP) and airway remodeling. Epithelial plasticity disrupts epithelial barrier function, stimulates release of fibroblastic growth factors, and remodels the extracellular matrix (ECM). This review will focus on recent work demonstrating how the hexosamine biosynthetic pathway (HBP) links innate inflammation to airway remodeling. The HBP is a core metabolic pathway of the unfolded protein response (UPR) responsible for protein N-glycosylation, relief of proteotoxic stress and secretion of ECM modifiers. We will overview findings that the IκB kinase (IKK)-NFκB pathway directly activates expression of the SNAI-ZEB1 mesenchymal transcription factor module through regulation of the Bromodomain Containing Protein 4 (BRD4) chromatin modifier. BRD4 mediates transcriptional elongation of SNAI1-ZEB as well as enhancing chromatin accessibility and transcription of fibroblast growth factors, ECM and matrix metalloproteinases (MMPs). In addition, recent exciting findings that IKK cross-talks with the UPR by controlling phosphorylation and nuclear translocation of the autoregulatory XBP1s transcription factor are presented. HBP is required for N glycosylation and secretion of ECM components that play an important signaling role in airway remodeling. This interplay between innate inflammation, metabolic reprogramming and lower airway plasticity expands a population of subepithelial myofibroblasts by secreting fibroblastic growth factors, producing changes in ECM tensile strength, and fibroblast stimulation by MMP binding. Through these actions on myofibroblasts, EMP in lower airway cells produces expansion of the lamina reticularis and promotes airway remodeling. In this manner, metabolic reprogramming by the HBP mediates environmental insult-induced inflammation with remodeling in chronic airway diseases.

Updates on NET formation in health and disease.

Following a recent presentation at ATT Mallorca in May 2019, this paper gives insight into the current research of neutrophil extracellular traps (NETs) and their role in conditions of health and disease. Though NETs reportedly support disease progression and play a role in the development of autoimmune diseases, we argue that NETs are mandatory for the mammalian immune system. They are especially important to patrol and surveil outer and inner body surfaces and are capable to perform major anti-microbial activities. Neutrophils are the first cells to be recruited to wounds, where they form NETs and aggregated NETs (aggNETs). The latter close the wounds and are ever-present in skinfolds, where the integrity of the skin is impaired. On infected ocular surfaces NETs form an antimicrobial barrier, which prevents bacterial dissemination into the brain. In the oral cavity, NETs display anti-bacterial properties. Although NETs on internal body surfaces like ducts and vessels offer superficial surveillance, exaggerated aggNET formation may directly block vessels and ducts and thus cause thrombi and ductal occlusion, respectively. In the case of biliopancreatic ducts, clogging by aggNETs may even cause acute pancreatitis. Insufficient clearance of apoptotic remnants and NETs can lead to autoimmune diseases or unwanted, chronic inflammation. To prevent this, macrophages cloak dead cells, while apoptotic cells are cleared. We conclude that neutrophils, NETs and aggNETs can be considered double edged swords that orchestrate the innate immune response but carry the risk to precipitate autoimmunity and epithelial damage.

Natural IgM and TLR Agonists Switch Murine Splenic Pan-B to "Regulatory" Cells That Suppress Ischemia-Induced Innate Inflammation via Regulating NKT-1 Cells.

Natural IgM anti-leukocyte autoantibodies (IgM-ALAs) inhibit inflammation by several mechanisms. Here, we show that pan-B cells and bone marrow-derived dendritic cells (BMDCs) are switched to regulatory cells when pretreated ex vivo with IgM. B cells are also switched to regulatory cells when pretreated ex vivo with CpG but not with LPS. Pre-emptive infusion of such ex vivo induced regulatory cells protects C57BL/6 mice from ischemia-induced acute kidney injury (AKI) via regulation of in vivo NKT-1 cells, which normally amplify the innate inflammatory response to DAMPS released after reperfusion of the ischemic kidney. Such ex vivo induced regulatory pan-B cells and BMDC express low CD1d and inhibit inflammation by regulating in vivo NKT-1 in the context of low-lipid antigen presentation and by a mechanism that requires costimulatory molecules, CD1d, PDL1/PD1, and IL10. Second, LPS and CpG have opposite effects on induction of regulatory activity in BMDC and B cells. LPS enhances regulatory activity of IgM-pretreated BMDC but negates the IgM-induced regulatory activity in B cells, while CpG, with or without IgM pretreatment, induces regulatory activity in B cells but not in BMDC. Differences in the response of pan-B and dendritic cells to LPS and CpG, especially in the presence of IgM-ALA, may have relevance during infections and inflammatory disorders where there is an increased IgM-ALA and release of TLRs 4 and 9 ligands. Ex vivo induced regulatory pan-B cells could have therapeutic relevance as these easily available cells can be pre-emptively infused to prevent AKI that can occur during open heart surgery or in transplant recipients receiving deceased donor organs.

Targeting Chromatin Remodeling in Inflammation and Fibrosis.

Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader. The RelA·BRD4·P-TEFb complex produces acute inflammation by regulating transcriptional elongation, which produces a rapid genomic response by inactive genes maintained in an open chromatin configuration engaged with hypophosphorylated RNA polymerase II. We describe recent studies that have linked prolonged activation of the RelA-BRD4 pathway with the epithelial-mesenchymal transition (EMT) by inducing a core of EMT corepressors, stimulating secretion of growth factors promoting airway fibrosis. The mesenchymal state produces rewiring of the kinome and reprogramming of innate responses toward inflammation. In addition, the core regulator Zinc finger E-box homeodomain 1 (ZEB1) silences the expression of the interferon response factor 1 (IRF1), required for type III IFN expression. This epigenetic silencing is mediated by the Enhancer of Zeste 2 (EZH2) histone methyltransferase. Because of their potential applications in cancer and inflammation, small-molecule inhibitors of NFκB/RelA, CDK9, BRD4, and EZH2 have been the targets of medicinal chemistry efforts. We suggest that disruption of the RelA·BRD4·P-TEFb pathway and EZH2 methyltransferase has important implications for reversing fibrosis and restoring normal mucosal immunity in chronic inflammatory diseases.

Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.

Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH.