Neutrophils in Psoriasis Chiang, Chih-Chao; Cheng, Wei-Jen; Korinek, Michal ...
Frontiers in immunology,
10/2019, Letnik:
10
Journal Article
Recenzirano
Odprti dostop
Neutrophils are the most abundant innate immune cells. The pathogenic roles of neutrophils are related to chronic inflammation and autoimmune diseases. Psoriasis is a chronic systemic inflammatory ...disease affecting ~2-3% of the world population. The abundant presence of neutrophils in the psoriatic skin lesions serves as a typical histopathologic hallmark of psoriasis. Recent reports indicated that oxidative stress, granular components, and neutrophil extracellular traps from psoriatic neutrophils are related to the initial and maintenance phases of psoriasis. This review provides an overview on the recent (up to 2019) advances in understanding the role of neutrophils in the pathophysiology of psoriasis, including the effects of respiratory burst, degranulation, and neutrophil extracellular trap formation on psoriatic immunity and the clinical relationships.
The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key ...roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed.
Gut barrier disruption and chronic disease Martel, Jan; Chang, Shih-Hsin; Ko, Yun-Fei ...
Trends in endocrinology and metabolism,
April 2022, 2022-04-00, 20220401, Letnik:
33, Številka:
4
Journal Article
Recenzirano
The intestinal barrier protects the host against gut microbes, food antigens, and toxins present in the gastrointestinal tract. However, gut barrier integrity can be affected by intrinsic and ...extrinsic factors, including genetic predisposition, the Western diet, antibiotics, alcohol, circadian rhythm disruption, psychological stress, and aging. Chronic disruption of the gut barrier can lead to translocation of microbial components into the body, producing systemic, low-grade inflammation. While the association between gut barrier integrity and inflammation in intestinal diseases is well established, we review here recent studies indicating that the gut barrier and microbiota dysbiosis may contribute to the development of metabolic, autoimmune, and aging-related disorders. Emerging interventions to improve gut barrier integrity and microbiota composition are also described.
Maintenance of gut barrier integrity is indispensable for health as the gut barrier protects the host against gut microbes, food antigens, and toxins.Many factors such as enteric infection, antibiotics, low-fiber diets, circadian rhythm disruption, and psychological stress can affect gut barrier integrity and lead to systemic, low-grade inflammation due to translocation of bacteria and their components.While the body can resist transient gut barrier disruption, it may be overwhelmed by mild insult due to genetic predisposition, chronic stress, and aging, which may contribute to the development of autoimmune, metabolic, and mental health disorders.Consideration of the various intrinsic and extrinsic factors that affect gut barrier integrity and microbiota composition is needed to maintain or restore human health.
Acute respiratory distress syndrome (ARDS) is difficult to treat and is associated with a high mortality rate. The most severe form of coronavirus disease 2019 (COVID-19) also leads to ...life-threatening ARDS. Neutrophil counts are positively correlated with disease severity in ARDS. Neutrophil activation not only plays a significant role in immune defense against infections, but also causes tissue damage and leads to inflammatory diseases. Activated neutrophils rapidly migrate to inflamed lung tissue, releasing toxic granular contents and generating neutrophil extracellular traps. In the last few decades, it has become apparent that neutrophils occupy a central role in ARDS pathology. In this review, we summarize the neutrophil inflammatory responses and their relationships to ARDS. According to the current literature, understanding the function of neutrophils may be helpful in the treatment of ARDS.
Background and Purpose
Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3′‐dihydroxy‐2′,6′‐bis(p‐hydroxybenzyl)‐5‐methoxybibenzyl), a natural bibenzyl, ...extracted from the Bletilla plant, exhibits anti‐inflammatory, antibacterial, and antimitotic effects. In this study, we evaluated the therapeutic effects of bletinib in human neutrophilic inflammation and LPS‐mediated ALI in mice.
Experimental Approach
In human neutrophils activated with the formyl peptide (fMLP), we assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Immunoblotting was used to measure phosphorylation of Src family kinases (SFKs) and downstream proteins. Finally, a LPS‐induced ALI model in male BALB/c mice was used to investigate the potential therapeutic effects of bletinib treatment.
Key Results
In activated human neutrophils, bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton's tyrosine kinase (Btk). In mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after bletinib treatment.
Conclusion and Implications
Bletinib regulates neutrophilic inflammation by inhibiting the SFK‐Btk‐Vav pathway. Bletinib ameliorates LPS‐induced ALI in mice. Further biochemical optimisation of bletinib may be a promising strategy for the development of novel therapeutic agents for inflammatory diseases.
This review describes targeting neutrophils as a potential therapeutic strategy for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19), a pandemic caused ...by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutrophil counts are significantly elevated in patients with COVID-19 and significantly correlated with disease severity. The neutrophil-to-lymphocyte ratio can serve as a clinical marker for predicting fatal complications related to ARDS in patients with COVID-19. Neutrophil-associated inflammation plays a critical pathogenic role in ARDS. The effector functions of neutrophils, acting as respiratory burst oxidants, granule proteases, and neutrophil extracellular traps, are linked to the pathogenesis of ARDS. Hence, neutrophils can not only be used as pathogenic markers but also as candidate drug targets for COVID-19 associated ARDS.
Neutrophils, which are the most abundant circulating leukocytes in humans, are the first line of defense against bacterial and fungal infections. Recent studies have reported the role and importance ...of neutrophils in cancers. Glioma and brain metastases are the most common malignant tumors of the brain. The tumor microenvironment (TME) in the brain is complex and unique owing to the brain-blood barrier or brain-tumor barrier, which may prevent drug penetration and decrease the efficacy of immunotherapy. However, there are limited studies on the correlation between brain cancer and neutrophils. This review discusses the origin and functions of neutrophils. Additionally, the current knowledge on the correlation between neutrophil-to-lymphocyte ratio and prognosis of glioma and brain metastases has been summarized. Furthermore, the implications of tumor-associated neutrophil (TAN) phenotypes and the functions of TANs have been discussed. Finally, the potential effects of various treatments on TANs and the ability of neutrophils to function as a nanocarrier of drugs to the brain TME have been summarized. However, further studies are needed to elucidate the complex interactions between neutrophils, other immune cells, and brain tumor cells.
Background and Purpose
Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. An overwhelming immune response by neutrophils is a ...key feature in infective or sterile ARDS. The formyl peptide receptor 1 (FPR1) is a crucial damage‐sensing receptor for inflammatory reactions in the initiation and progression of neutrophil‐mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited.
Experimental Approach
Human neutrophils were used to explore the anti‐inflammatory effects of cyclic lipopeptide anteiso‐C13‐surfactin (IA‐1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide‐induced model of ARDS in mice was used to determine the therapeutic potential of IA‐1 in ARDS. Lung tissues were harvested for histology analyses.
Key Results
The lipopeptide IA‐1 inhibited immune responses of neutrophils, including respiratory burst, degranulation, and expression of adhesion molecules. IA‐1 inhibited the binding of N‐formyl peptides to FPR1 in human neutrophils and in hFPR1‐transfected HEK293 cells. We identified IA‐1 as a competitive FPR1 antagonist, thus diminishing the downstream signalling pathways involving calcium, mitogen‐activated protein kinases and Akt. Furthermore, IA‐1 ameliorated the inflammatory damage to lung tissue, by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice.
Conclusion and Implications
The lipopeptide IA‐1 could serve as a therapeutic option for ARDS by inhibiting FPR1‐mediated neutrophilic injury.
Anteiso‐C13‐surfactin from marine Bacillus amyloliquefaciens inhibits neutrophilic immune responses through blocking FPR1 and attenuates lung inflammatory injury in neutrophil‐dominant ARDS.
Sepsis is a life‐threatening condition that can progress to septic shock as the body's extreme response to pathogenesis damages its own vital organs. Staphylococcus aureus (S. aureus) accounts for ...50% of nosocomial infections, which are clinically treated with antibiotics. However, methicillin‐resistant strains (MRSA) have emerged and can withstand harsh antibiotic treatment. To address this problem, curcumin (CCM) is employed to prepare carbonized polymer dots (CPDs) through mild pyrolysis. Contrary to curcumin, the as‐formed CCM‐CPDs are highly biocompatible and soluble in aqueous solution. Most importantly, the CCM‐CPDs induce the release of neutrophil extracellular traps (NETs) from the neutrophils, which entrap and eliminate microbes. In an MRSA‐induced septic mouse model, it is observed that CCM‐CPDs efficiently suppress bacterial colonization. Moreover, the intrinsic antioxidative, anti‐inflammatory, and anticoagulation activities resulting from the preserved functional groups of the precursor molecule on the CCM‐CPDs prevent progression to severe sepsis. As a result, infected mice treated with CCM‐CPDs show a significant decrease in mortality even through oral administration. Histological staining indicates negligible organ damage in the MRSA‐infected mice treated with CCM‐CPDs. It is believed that the in vivo studies presented herein demonstrate that multifunctional therapeutic CPDs hold great potential against life‐threatening infectious diseases.
The biocompatible curcumin‐derived carbonized polymer dots (CCM‐CPDs) stimulate neutrophils to release traps that capture and eradicate harmful microbes. Tested on mice with MRSA‐induced sepsis, CCM‐CPDs notably curtailed bacterial growth, prevents severe septic developments, and significantly reduces mortality rates. Histological analysis reveals minimal organ damage in treated mice. Harnessing the power of natural phytochemicals to create carbonized nanomaterials to boost immune responses, offers promising potential against severe infectious diseases, marking a significant stride in combating antibiotic‐resistant pathogens.
ABSTRACT
Psoriasis is an inflammatory autoimmune skin disorder possessing a complex etiology related to genetic and environmental triggers. Keratinocytes show a potential role for the origin of ...psoriasis. In this study, we estimated the efficiency of 2 anthranilate derivatives—(E)‐4‐(N‐{2‐1‐(hydroxyimino)ethylphenyl}sulfamoyl)phenyl pivalate (HFP031) and butyl 2‐2‐(2‐fluorophenyl)acetamidobenzoate (HFP034)—on psoriasis amelioration in a mouse model. The results showed that topical treatment with both compounds could attenuate epidermal thickness and scaling in an imiquimod (IMQ)‐induced psoriasis mouse model via decreased expression of cytokines and chemokines C‐X‐C chemokine ligand (CXCL)1 and CXCL2, leading to the reduction of neutrophilic abscess in the skin. The in vivo cutaneous absorption of HFP034 was 7.6‐fold greater than that of HFP031. Both compounds caused negligible irritation on healthy mouse skin. In addition, we examined the effect of the anthranilate derivatives on chemokine expression in IMQ‐treated HaCaT keratinocytes. Our results elucidated a mechanism for anti‐inflammatory activity of HFP034 that involved the elevation of intracellular cAMP concentration, suppression of NF‐κB activity, and attenuation of neutrophil chemoattractant expression. These results suggest that HFP034 could increase the cutaneous concentration of cAMP to suppress neutrophil infiltration into the skin. Topically applied HFP034 may demonstrate a potential for future clinical application as a novel therapy for psoriasis treatment.—Lin, Z.‐C., Hsieh, P.‐W., Hwang, T.‐L., Chen, C.‐Y., Sung, C. T., Fang, J.‐Y. Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration. FASEB J. 32, 6783–6795 (2018). www.fasebj.org
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