-
Veterinary Medicine (Auckland, N.Z.) 2024Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial,... (Review)
Review
Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.
PubMed: 38371487
DOI: 10.2147/VMRR.S412570 -
Biochimica Et Biophysica Acta.... Apr 2024Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the...
Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the formation of pro-secretory ion transport characterised by elevated basal Cl current. Studies using human sinonasal epithelial cells treated with HDM extract report a higher protease activated receptor-2 (PAR-2) agonist-induced calcium mobilisation that may be related to airway sensitisation by allergen-associated proteases. Herein, this study aimed to investigate the effect of HDM on Ca signalling and inflammatory responses in asthmatic airway epithelial cells. Primary bronchial epithelial cells (hPBECs) from asthma donors cultured at air-liquid interface were used to assess electrophysiological, Ca signalling and inflammatory responses. Differences were observed regarding Ca signalling in response to PAR-2 agonist 2-Furoyl-LIGRLO-amide (2-FLI), and equivalent short-circuit current (I) in response to trypsin and 2-FLI, in ALI-asthma and healthy hPBECs. HDM treatment led to increased levels of intracellular cations (Ca, Na) and significantly reduced the 2-FLI-induced change of I in asthma cells. Apical HDM-induced Ca mobilisation was found to mainly involve the activation of PAR-2 and PAR-4-associated store-operated Ca influx and TRPV1. In contrast, PAR-2, PAR-4 antagonists and TRPV1 antagonist only showed slight impact on basolateral HDM-induced Ca mobilisation. HDM trypsin-like serine proteases were the main components leading to non-amiloride sensitive I and also increased interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) from asthma hPBECs. These studies add further insight into the complex mechanisms associated with HDM-induced alterations in cell signalling and their relevance to pathological changes within asthma.
Topics: Humans; Animals; Alarmins; Trypsin; Asthma; Epithelial Cells; Allergens; Pyroglyphidae
PubMed: 38367901
DOI: 10.1016/j.bbadis.2024.167079 -
Journal of Investigational Allergology... Feb 2024
EPI-SURVEY. Grade of awareness of Spanish allergist, hospital pharmacist, and pulmonologists on the relevance of bronchial epithelium and alarmins in the pathogenesis and management of severe asthma.
PubMed: 38353099
DOI: 10.18176/jiaci.0997 -
International Journal of Molecular... Jan 2024MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released...
MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released upon epithelial damage. Adenosine triphosphate (ATP) accumulates at sites of tissue injury and is known to modulate MC activities. This study investigated how an inflammatory tissue environment rich in IL-33 modulates the ATP-mediated activation of MCs. Human primary MCs primed with IL-33 displayed a strongly increased response to ATP but not ADP. This resulted in increased degranulation, IL-8 release, and pERK1/2 signalling. Such effects are unique to IL-33 stimulation and not shared by the epithelial alarmin, TSLP. MC exposure to IL-33 also increased membrane expression of purinergic and ATP-binding P2X receptors. The use of selective P2X receptor inhibitors identified P2X7 receptor as the key mediator of the enhanced ATP-induced ERK1/2 signalling and degranulation in IL-33-primed MCs. Whilst the inhibition of P2X1 and P2X4 receptors had no effect on MC degranulation, inhibiting these receptors together with P2X7 resulted in further decreased MC-mediated degranulation. These data therefore point toward the potential mechanisms by which IL-33 contributes to the modulation of ATP-mediated activation in human MCs.
Topics: Humans; Adenosine Triphosphate; Cell Degranulation; Interleukin-33; Mast Cells; Receptors, Purinergic P2X7; Signal Transduction
PubMed: 38339008
DOI: 10.3390/ijms25031730 -
Nature Communications Feb 2024Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a...
Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. The molecular details of complex formation were still elusive. Here we show by an integrated structural approach that frHMGB1•CXCL12 is a fuzzy heterocomplex. Unlike previous assumptions, frHMGB1 and CXCL12 form a dynamic equimolar assembly, with structured and unstructured frHMGB1 regions recognizing the CXCL12 dimerization surface. We uncover an unexpected role of the acidic intrinsically disordered region (IDR) of HMGB1 in heterocomplex formation and its binding to CXCR4 on the cell surface. Our work shows that the interaction of frHMGB1 with CXCL12 diverges from the classical rigid heterophilic chemokines dimerization. Simultaneous interference with multiple interactions within frHMGB1•CXCL12 might offer pharmacological strategies against inflammatory conditions.
Topics: Humans; Chemokine CXCL12; HMGB1 Protein; Receptors, CXCR4; Inflammation; Signal Transduction
PubMed: 38331917
DOI: 10.1038/s41467-024-45505-7 -
Molecular Medicine (Cambridge, Mass.) Feb 2024In sepsis, intestinal barrier dysfunction is often caused by the uncontrolled death of intestinal epithelial cells (IECs). CD4CD8αα intraepithelial lymphocytes (IELs),...
BACKGROUND
In sepsis, intestinal barrier dysfunction is often caused by the uncontrolled death of intestinal epithelial cells (IECs). CD4CD8αα intraepithelial lymphocytes (IELs), a subtype of CD4 T cells residing within the intestinal epithelium, exert cytotoxicity by producing granzyme B (GrB) and perforin (Prf). Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently identified alarmin which stimulates TLR4 on immune cells to induce proinflammatory responses. Here, we hypothesized that eCIRP enhances CD4CD8αα IEL cytotoxicity and induces IEC death in sepsis.
METHODS
We subjected wild-type (WT) and CIRP mice to sepsis by cecal ligation and puncture (CLP) and collected the small intestines to isolate IELs. The expression of GrB and Prf in CD4CD8αα IELs was assessed by flow cytometry. IELs isolated from WT and TLR4 mice were challenged with recombinant mouse CIRP (eCIRP) and assessed the expression of GrB and Prf in CD4CD8αα by flow cytometry. Organoid-derived IECs were co-cultured with eCIRP-treated CD4CD8αα cells in the presence/absence of GrB and Prf inhibitors and assessed IEC death by flow cytometry.
RESULTS
We found a significant increase in the expression of GrB and Prf in CD4CD8αα IELs of septic mice compared to sham mice. We found that GrB and Prf levels in CD4CD8αα IELs were increased in the small intestines of WT septic mice, while CD4CD8αα IELs of CIRP mice did not show an increase in those cytotoxic granules after sepsis. We found that eCIRP upregulated GrB and Prf in CD4CD8αα IELs isolated from WT mice but not from TLR4 mice. Furthermore, we also revealed that eCIRP-treated CD4CD8αα cells induced organoid-derived IEC death, which was mitigated by GrB and Prf inhibitors. Finally, histological analysis of septic mice revealed that CIRP mice were protected from tissue injury and cell death in the small intestines compared to WT mice.
CONCLUSION
In sepsis, the cytotoxicity initiated by the eCIRP/TLR4 axis in CD4CD8αα IELs is associated with intestinal epithelial cell (IEC) death, which could lead to gut injury.
Topics: Animals; Mice; Intestinal Mucosa; Intestines; Intraepithelial Lymphocytes; Mice, Inbred C57BL; Sepsis; Toll-Like Receptor 4
PubMed: 38302880
DOI: 10.1186/s10020-024-00790-2 -
Biomolecules Dec 2023Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE...
Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.
Topics: Humans; HMGB1 Protein; Dilatation, Pathologic; Coronary Angiography; Prospective Studies; Cross-Sectional Studies; Endothelial Cells; Toll-Like Receptor 4; Coronary Artery Disease; Alarmins
PubMed: 38275751
DOI: 10.3390/biom14010010 -
Journal of Clinical Medicine Jan 2024Periodontitis is a chronic inflammatory disease. We have previously shown that salivary DNA is higher in patients with periodontitis. Neutrophil extracellular traps...
Periodontitis is a chronic inflammatory disease. We have previously shown that salivary DNA is higher in patients with periodontitis. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of chronic inflammatory diseases. The objective of this case-control study was to compare patients with periodontitis and healthy controls regarding the salivary concentrations of extracellular DNA and NET components. Unstimulated saliva samples were collected from 49 patients with periodontitis and 71 controls before an oral examination. Salivary extracellular DNA was isolated and quantified fluorometrically and using PCR. NET-associated markers were assessed using ELISA. We have found significantly higher concentrations of salivary extracellular DNA in samples from periodontitis patients (five-times higher for supernatant and three times for pellet). Our results show that patients also have three-times-higher salivary nucleosomes and NET-associated enzymes-myeloperoxidase and neutrophil elastase (both two-times higher). Neutrophil elastase and salivary DNA in the pellet correlated positively with the pocket depth/clinical attachment level in periodontitis patients (r = 0.31-weak correlation; = 0.03 and r = 0.41-moderate correlation, = 0.004). Correlations between salivary extracellular DNA and NET enzymes were positive and significant. Based on our results, the higher salivary extracellular DNA in periodontitis seems to be related to components of NETs, albeit with weak to moderate correlations indicating that NETs are produced in periodontitis and can play a role in its pathogenesis similarly to other inflammatory diseases. Further studies should prove this assumption with potential diagnostic and therapeutic consequences.
PubMed: 38256602
DOI: 10.3390/jcm13020468 -
PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications.International Journal of Molecular... Jan 2024Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved... (Review)
Review
Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed and Cochrane. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.
Topics: Humans; Pathogen-Associated Molecular Pattern Molecules; Sepsis; Alarmins; Immunity, Innate; PubMed
PubMed: 38256033
DOI: 10.3390/ijms25020962 -
International Journal of Molecular... Jan 2024Psoriasis is a chronic skin disorder that involves both innate and adaptive immune responses in its pathogenesis. Local tissue damage is a hallmark feature of psoriasis... (Review)
Review
Psoriasis is a chronic skin disorder that involves both innate and adaptive immune responses in its pathogenesis. Local tissue damage is a hallmark feature of psoriasis and other autoimmune diseases. In psoriasis, damage-associated molecular patterns (DAMPs) released by damaged local tissue act as danger signals and trigger inflammatory responses by recruiting and activating immune cells. They also stimulate the release of pro-inflammatory cytokines and chemokines, which exacerbate the inflammatory response and contribute to disease progression. Recent studies have highlighted the role of DAMPs as key regulators of immune responses involved in the initiation and maintenance of psoriatic inflammation. This review summarizes the current understanding of the immune mechanism of psoriasis, focusing on several important DAMPs and their mechanisms of action. We also discussed the potential of DAMPs as diagnostic and therapeutic targets for psoriasis, offering new insights into the development of more effective treatments for this challenging skin disease.
Topics: Humans; Psoriasis; Alarmins; Autoimmune Diseases; Cognition; Cytokines
PubMed: 38255845
DOI: 10.3390/ijms25020771