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Netea and colleagues provide a general guide to the cellular and humoral contributors to inflammation as well as the pathways that characterize inflammation in specific organs and tissues. Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues 1 , 2 , but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFβ negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury. In mouse and human, lung-specialized alveolar fibroblasts adopt multiple molecular states that are induced by pro-inflammatory and fibrotic signals and have diverse protective roles against lung injury.

Extracellular ATP released from cells during inflammatory responses predominantly functions as a signalling molecule through the activation of purinergic P2 receptors and contributes to both beneficial and detrimental inflammatory responses; this review examines P2 receptor signalling via ATP and its effect on the outcome of inflammatory and infectious diseases. Two sides to purinergic signalling The role of purinergic signalling events in the context of inflammatory diseases is ambivalent: purinergic P2 receptors, activated by ATP and some other nucleotides, are critical in mounting an appropriate inflammatory response against invading pathogens or tumours, yet P2X/P2Ysignalling can cause the initiation and perpetuation of chronic inflammation in conditions such as asthma, chronic lung diseases, or inflammatory bowel disease. This Review focuses on the health aspects of the complex biology of ATP receptor signalling. The authors conclude that pharmacological amplification of extracellular ATP signalling holds promise as a treatment for cancer and infectious disease and that strategies that block P2 receptor signalling, promote extracellular conversion of ATP to adenosine and activate adenosine receptors could be effective in treating acute or chronic inflammatory diseases. Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Y signalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases.

Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with radiographic and pain progression. Several OA risk factors, including ageing, obesity, trauma and mechanical loading, play a role in OA pathogenesis, likely by modifying synovial biology. In addition, other factors, such as mitochondrial dysfunction, damage-associated molecular patterns, cytokines, metabolites and crystals in the synovium, activate synovial cells and mediate synovial inflammation. An understanding of the activated pathways that are involved in OA-related synovial inflammation could form the basis for the stratification of patients and the development of novel therapeutics. This Review focuses on the biology of the OA synovium, how the cells residing in or recruited to the synovium interact with each other, how they become activated, how they contribute to OA progression and their interplay with other joint structures.This Review examines the biology of synovial inflammation, the cell types involved, their interactions and the role of synovitis in the development and progression of osteoarthritis.

This study aimed to elucidate the cellular and molecular mechanisms of GSDME in GSDMD independent nucleus pulposus (NP) cell pyroptosis. We analyzed microarray datasets to identify differentially expressed genes (DEGs) in the progression of intervertebral disc degeneration (IDD) and conducted Gene Ontology analysis to elucidate DEGs-participated biological processes. We utilized lipopolysaccharides (LPS) to treat human primary NP cells to establish pyroptosis cell model. And siRNA was used to simulate a GSDMD-deficient environment. We used several regulators to figure out how GSDME was participate in pyroptosis via a GSDMD independent pathway. The molecular docking was conducted to identify compound that could possibly bind to GSDME and suppress its cleavage. Finally, Ocifisertib was intraperitoneally administered into IDD rat model to explore its therapeutic potential. Pyroptosis was activated in IDD. In vitro, LPS induced NP cell pyroptosis by promoting the cleavage of GSDMD and GSDME. In the absence of GSDMD, the cleavage of GSDME compensatively upregulated to mediate pyroptosis. Ocifisertib alleviated pyroptosis-mediated IDD by inhibiting GSDME cleavage in annulus fibrosus puncture-induced IDD rat model. Our study provides evidence that the cleavage of GSDME aggravates IDD by accelerating NP cell pyroptosis and demonstrates that Ocifisertib has therapeutic potential in IDD treatment.

The aetiology of septic acute kidney injury (AKI) is not completely elucidated. Early identification of AKI in septic patients is considered to improve survival rate since it allows rapid treatment onset. We evaluated clinical, haematological, urinary, B-mode, spectral Doppler, and contrast-enhanced ultrasound variables in 20 bitches with pyometra as sepsis models and 12 healthy controls. All animals with pyometra presented some degree of renal damage on histological examination; however, sequential organ failure assessment (SOFA) classified only 40% cases with sepsis. AKI derived from systemic infection was identified in 57% of cases with hypoperfusion and in 22% with inflammation, being an affection of multifactorial origin. Among the evaluated parameters, urinary protein/creatinine ratio >0.15, serum albumin <2.94 mg/dL, time-averaged minimum velocity <21.5 cm/s, renal length/aorta diameter ratio >5.93, pulsatility index >1.53, haematocrit <45%, time-averaged maximum velocity <45.7 cm/s, haemoglobin <16 g/dL, leukocytes >12.53 × 10 3 /uL, and cortical contrast peak intensity <69%, in the order of accuracy, are significant indicators of septic AKI with an accuracy >80%. Thus, AKI is a very prevalent condition in septic patients, derived mainly from changes in renal perfusion and inflammation. Additionally, reviewing the SOFA score parameters is suggested to identify renal failure.

Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE-sequencing; combining surface proteomics with in-depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell findings. For the first time we show that human tendon harbours at least five distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T-cells, and monocytes. These consist of KRT7/SCX + cells expressing microfibril associated genes, PTX3 + cells co-expressing high levels of pro-inflammatory markers, APOD + fibro–adipogenic progenitors, TPPP3/PRG4 + chondrogenic cells, and ITGA7 + smooth muscle-mesenchymal cells. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro-inflammatory markers PTX3 , CXCL1, CXCL6, CXCL8, and PDPN by microfibril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33.

Regulatory T-cell (Treg)/T-helper 17 (T h 17) cell balance plays an important role in the progression of rheumatoid arthritis (RA). Our study explored the protective effect of protectin DX (PDX), which restored Treg/T h 17 cell balance in RA, and the role of the nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathway in this process. Using mass spectrometry, we discovered that level of PDX decreased in active-RA patients and increased in inactive-RA patients compared with HCs, and serum PDX was a potential biomarker in RA activity detection (area under the curve [AUC] = 0.86). In addition, a collagen-induced arthritis (CIA) mice model was constructed and PDX obviously delayed RA progression in the CIA model, upregulating Tregs and anti-inflammatory cytokines while downregulating T h 17 cells and pro-inflammatory cytokines. Moreover, NLRP3 knockout and rescue experiments demonstrated that NLRP3 participated in PDX-mediated Treg/T h 17 cell balance restoration, joint injury amelioration and inflammatory-response attenuation using Nlrp3 −/− mice. Furthermore, microarray and verified experiments confirmed that PDX reduced NLRP3 expression via miRNA-20a (miR-20a). In summary, we confirmed for the first time that PDX could effectively ameliorate CIA progression by restoring Treg/T h 17 cell balance, which was mediated by inhibition of the NLRP3 inflammasome pathway via miR-20a.

The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I 2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.

Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.