scholarly journals IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule

2021 ◽  
Vol 12 ◽  
Author(s):  
Jorge H. Tabares-Guevara ◽  
Julio C. Jaramillo ◽  
Laura Ospina-Quintero ◽  
Christian A. Piedrahíta-Ochoa ◽  
Natalia García-Valencia ◽  
...  
Keyword(s):  
Small Molecule ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Clinical Effects ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Immune Effector ◽  
Cytokine Balance ◽  
The One ◽  
Deficient Mice

One of the interventional strategies to reestablish the immune effector/regulatory balance, that is typically altered in chronic inflammatory diseases (CID), is the reinforcement of endogenous immunomodulatory pathways as the one triggered by interleukin (IL)-10. In a recent work, we demonstrated that the subcutaneous (sc) administration of an IL-10/Treg-inducing small molecule-based formulation, using a repetitive microdose (REMID) treatment strategy to preferentially direct the effects to the regional immune system, delays the progression of atherosclerosis. Here we investigated whether the same approach using other IL-10-inducing small molecule, such as the safe, inexpensive, and widely available polyphenol curcumin, could induce a similar protective effect in two different CID models. We found that, in apolipoprotein E deficient mice, sc treatment with curcumin following the REMID strategy induced atheroprotection that was not consequence of its direct systemic lipid-modifying or antioxidant activity, but instead paralleled immunomodulatory effects, such as reduced proatherogenic IFNγ/TNFα-producing cells and increased atheroprotective FOXP3+ Tregs and IL-10-producing dendritic and B cells. Remarkably, when a similar strategy was used in the neuroinflammatory model of experimental autoimmune encephalomyelitis (EAE), significant clinical and histopathological protective effects were evidenced, and these were related to an improved effector/regulatory cytokine balance in restimulated splenocytes. The essential role of curcumin-induced IL-10 for neuroprotection was confirmed by the complete abrogation of the clinical effects in IL-10-deficient mice. Finally, the translational therapeutic prospection of this strategy was evidenced by the neuroprotection observed in mice starting the treatment one week after disease triggering. Collectively, results demonstrate the power of a simple natural IL-10-inducing small molecule to tackle chronic inflammation, when its classical systemic and direct pharmacological view is shifted towards the targeting of regional immune cells, in order to rationally harness its immunopharmacological potential. This shift implies that many well-known IL-10-inducing small molecules could be easily reformulated and repurposed to develop safe, innovative, and accessible immune-based interventions for CID.

scholarly journals Caspase-11 Mediates Oligodendrocyte Cell Death and Pathogenesis of Autoimmune-Mediated Demyelination

2001 ◽  
Vol 193 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Shin Hisahara ◽  
Junying Yuan ◽  
Takashi Momoi ◽  
Hideyuki Okano ◽  
Masayuki Miura
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Cell Death ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Deficient Mice ◽  
Experimental Autoimmune

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11–deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11–deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

scholarly journals Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

2021 ◽  
Vol 22 (11) ◽  
pp. 5770
Author(s):  
Eunhye Ji ◽  
Sahmin Lee
Keyword(s):  
Cardiovascular Diseases ◽  
Apolipoprotein B ◽  
Animal Studies ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Clinical Effects ◽  
Rheumatic Arthritis ◽  
Chronic Inflammatory Diseases ◽  
Cholesterol Levels ◽  
Tnf Α

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.

scholarly journals Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

2021 ◽  
Vol 12 ◽  
Author(s):  
Guan Yang ◽  
Luc Van Kaer
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Nerve Fibers ◽  
Therapeutic Approaches ◽  
Autoimmune Encephalomyelitis ◽  
Autoimmune And Inflammatory Diseases ◽  
The Central Nervous System

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.

scholarly journals Chromatin Regulator SRG3 Overexpression Protects against LPS/D-GalN-Induced Sepsis by Increasing IL10-Producing Macrophages and Decreasing IFNγ-Producing NK Cells in the Liver

2021 ◽  
Vol 22 (6) ◽  
pp. 3043
Author(s):  
Sung Won Lee ◽  
Hyun Jung Park ◽  
Jungmin Jeon ◽  
Yun Hoo Park ◽  
Tae-Cheol Kim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Nkt Cells ◽  
M2 Macrophage ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Chromatin Regulator ◽  
Hepatic Macrophages

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3β-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3β-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3β-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.

Role of Exosomes in the Exchange of Spermatozoa after Leaving the Seminiferous Tubule: A Review

2020 ◽  
Vol 21 (5) ◽  
pp. 330-338
Author(s):  
Luming Wu ◽  
Yuan Ding ◽  
Shiqiang Han ◽  
Yiqing Wang
Keyword(s):  
Drug Delivery ◽  
Plasma Membrane ◽  
Seminiferous Tubule ◽  
Metabolic Diseases ◽  
Inflammatory Diseases ◽  
Multivesicular Bodies ◽  
Extensive Search ◽  
Neurological Research ◽  
The One

Background: Exosomes are extracellular vesicles (EVs) released from cells upon fusion of an intermediate endocytic compartment with the plasma membrane. They refer to the intraluminal vesicles released from the fusion of multivesicular bodies with the plasma membrane. The contents and number of exosomes are related to diseases such as metabolic diseases, cancer and inflammatory diseases. Exosomes have been used in neurological research as a drug delivery tool and also as biomarkers for diseases. Recently, exosomes were observed in the seminal plasma of the one who is asthenozoospermia, which can affect sperm motility and capacitation. Objective: The main objective of this review is to deeply discuss the role of exosomes in spermatozoa after leaving the seminiferous tubule. Methods: We conducted an extensive search of the literature available on relationships between exosomes and exosomes in spermatozoa on the bibliographic database. Conclusion: : This review thoroughly discussed the role that exosomes play in the exchange of spermatozoa after leaving the seminiferous tubule and its potential as a drug delivery tool and biomarkers for diseases as well.

scholarly journals IL-6 Is Not Absolutely Essential for the Development of a TH17 Immune Response after an Aerosol Infection with Mycobacterium tuberculosis H37rv

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 9
Author(s):  
Kristina Ritter ◽  
Jan Christian Sodenkamp ◽  
Alexandra Hölscher ◽  
Jochen Behrends ◽  
Christoph Hölscher
Keyword(s):  
Immune Response ◽  
Inflammatory Diseases ◽  
Mycobacterial Infection ◽  
Minor Effect ◽  
Mycobacterium Tuberculosis H37rv ◽  
Th 17 ◽  
Anti Inflammatory ◽  
A Minor ◽  
Aerosol Infection ◽  
Deficient Mice

Anti-inflammatory treatment of chronic inflammatory diseases often increases susceptibility to infectious diseases such as tuberculosis (TB). Since numerous chronic inflammatory and autoimmune diseases are mediated by interleukin (IL)-6-induced T helper (TH) 17 cells, a TH17-directed anti-inflammatory therapy may be preferable to an IL-12-dependent TH1 inhibition in order to avoid reactivation of latent infections. To assess, however, the risk of inhibition of IL-6-dependent TH17-mediated inflammation, we examined the TH17 immune response and the course of experimental TB in IL-6- and T-cell-specific gp130-deficient mice. Our study revealed that the absence of IL-6 or gp130 on T cells has only a minor effect on the development of antigen-specific TH1 and TH17 cells. Importantly, these gene-deficient mice were as capable as wild type mice to control mycobacterial infection. Together, in contrast to its key function for TH17 development in other inflammatory diseases, IL-6 plays an inferior role for the generation of TH17 immune responses during experimental TB.

scholarly journals POS0083 USEFUL EXPERIENCE OF RHEUMATOLOGISTS FOR UNDERSTANDING OF THE DISEASE ORIGIN AND APPROACHES TO THERAPY IN FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 249.2-250
Author(s):  
I. Nikishina ◽  
S. Arsenyeva ◽  
V. Matkava ◽  
A. Arefieva ◽  
M. Kaleda ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Kinase Inhibitor ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Rapid Progression ◽  
Time Duration ◽  
Long Term Follow Up ◽  
Vertebral Bodies ◽  
The One

Background:Many monogenic genetic conditions, such as auto-inflammatory diseases (AIDs), have similar clinical manifestations and immunopathogenesis to “classic” rheumatic diseases (RD). Such cases may include Fibrodysplasia ossificans progressiva (FOP), an extremely rare genetic disease, which, according to our previous study and data from other authors1, may represent an example of AID with catastrophic heterotopic ossification due to a mutation in the ACVR1 gene. it seems that the experience of rheumatologists, especially children’s ones, will be useful in the treatment of FOP.Objectives:To analyzed the dynamics of clinical manifestations and to therapy approaches including target anti-inflammatory drug Tofacitinib (TOFA) in the one of the world’s largest groups of patients (pts) with FOP.Methods:The study was based on the analysis retrospective and prospective observation of the 35 pts (17 males and 18 females) with a verified diagnosis of FOP for the period from 1998 to 2020. In 9 pts with severe course of FOP TOFA administration were evaluated.Results:In all 35 pts the diagnosis was verified by “classic” FOP phenotype: malformed great toes in 33 pts (94,3%); short malformed thumbs-8 (22.8%); peripheral osteochondromas-20 (57.1%); abnormalities of the cervical spine-32 (91.4%), multiple heterotopic ossifications-32 (91,4%). Genetic tests were done in 26, it confirmed mutation in the ACVR1 gene in 100%. Long term follow-up detected a lot of spondyloarthritis-like signs similar to the manifestation of RD: ankylosis of the facet joints and vertebral bodies (by the type of syndesmophytes) in most pts, sacroiliitis, confirmed by radiological methods (X-ray, CT, MRI), gradual ankylosis in the peripheral joints in 18 (56.4%), synovitis in large joints in 8 (25%) pts (knee and hip mostly). In 9 pts with the most difficult course with rapid progression of ossification due to continuous flares despite the NSAIDs and steroids intake, we tried to use TOFA after the approval of the local Ethic Committee. We use the similar dose to randomized trial for JIA (up to 5 mg twice a day). The first patient was 16 y.o. at the time of TOFA administration in December 2019, the age of the other pts was from 2 to 12 y.o. By present time duration of TOFA therapy is from 6 to 15 mo. For the previous 6 months before TOFA initiation the number of flares was in average 8 per patient. After 6 months of TOFA treatment the number of new flares decreased to 0-1, except youngest patient of 2 y.o. in whom the number of flares decreased from 10 to 4 per the same period. In all 9 pts we minimize the dose or completely stop the steroids. New nodes formation stopped immediately in most pts and also the significant motion improvement of large (shoulder) joints were established. Drug tolerance was good in all pts, no AE were registered. But despite the good clinical effect without new heterotopic ossification in our first patient, we found continuous intraskeletal ossification between vertebral bodies, facet and sacroiliac joints in MRI.Conclusion:We are confident that the processes of heterotopic ossification in FOP are very similar to new born formation phenomenon in spondyloarthritis and reliable suppression of inflammation can interrupt the progression of the disease. We used similar justifications to our colleagues for the use of anti-cytokine drugs, but used a JAK-kinase inhibitor, it was extremely important the oral rout of drug administration and possibility to escape any injections in FOP. TOFA demonstrated positive effect and safety in children with severe course of FOP. It showed their advantages over the use of steroids and possibility to inhibit the rate of progression.References:[1]R.Haviv et al. Is fibrodysplasia ossificans progressiva aninterleukin-1 driven auto-inflammatory syndrome? Pediatric Rheumatology (2019) 17:84 //doi.org/10.1186/s12969-019-0386-6Disclosure of Interests:None declared.

scholarly journals Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

2021 ◽  
Vol 14 (6) ◽  
pp. 522
Author(s):  
Mohammad S. Akhter ◽  
Mohammad A. Uddin ◽  
Khadeja-Tul Kubra ◽  
Nektarios Barabutis
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Intratracheal Instillation ◽  
Hsp90 Inhibitor ◽  
Molecular Pathways ◽  
Protective Effects ◽  
Inflammatory Pathways ◽  
Cytokines And Chemokines ◽  
The Unfolded Protein Response ◽  
Mouse Lungs

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause thousands of deaths every year and are associated with high mortality rates (~40%) due to the lack of efficient therapies. Understanding the molecular mechanisms associated with those diseases will most probably lead to novel therapeutics. In the present study, we investigated the effects of the Hsp90 inhibitor AUY-922 in the major inflammatory pathways of mouse lungs. Mice were treated with LPS (1.6 mg/kg) via intratracheal instillation for 24 h and were then post-treated intraperitoneally with AUY-922 (10 mg/kg). The animals were examined 48 h after AUY-922 injection. LPS activated the TLR4-mediated signaling pathways, which in turn induced the release of different inflammatory cytokines and chemokines. AUY-922 suppressed the LPS-induced inflammation by inhibiting major pro-inflammatory pathways (e.g., JAK2/STAT3, MAPKs), and downregulated the IL-1β, IL-6, MCP-1 and TNFα. The expression levels of the redox regulator APE1/Ref1, as well as the DNA-damage inducible kinases ATM and ATR, were also increased after LPS treatment. Those effects were counteracted by AUY-922. Interestingly, this Hsp90 inhibitor abolished the LPS-induced pIRE1α suppression, a major component of the unfolded protein response. Our study elucidates the molecular pathways involved in the progression of murine inflammation and supports our efforts on the development of new therapeutics against lung inflammatory diseases and sepsis.

scholarly journals Intermittent rolling is a defect of the extravasation cascade caused by Myosin1e-deficiency in neutrophils

2019 ◽  
Vol 116 (52) ◽  
pp. 26752-26758 ◽  
Author(s):  
Eduardo Vadillo ◽  
Sandra Chánez-Paredes ◽  
Hilda Vargas-Robles ◽  
Idaira María Guerrero-Fonseca ◽  
Ramón Castellanos-Martínez ◽  
...  
Keyword(s):  
Vascular Endothelium ◽  
Actin Polymerization ◽  
Inflammatory Diseases ◽  
Chimeric Mice ◽  
Rolling Velocity ◽  
Chronic Inflammatory Diseases ◽  
Neutrophil Extravasation ◽  
Cytoskeletal Dynamics ◽  
Adhesive Interactions ◽  
Deficient Mice

Neutrophil extravasation is a migratory event in response to inflammation that depends on cytoskeletal dynamics regulated by myosins. Myosin-1e (Myo1e) is a long-tailed class-I myosin that has not yet been studied in the context of neutrophil–endothelial interactions and neutrophil extravasation. Intravital microscopy of TNFα-inflamed cremaster muscles in Myo1e-deficient mice revealed that Myo1e is required for efficient neutrophil extravasation. Specifically, Myo1e deficiency caused increased rolling velocity, decreased firm adhesion, aberrant crawling, and strongly reduced transmigration. Interestingly, we observed a striking discontinuous rolling behavior termed “intermittent rolling,” during which Myo1e-deficient neutrophils showed alternating rolling and jumping movements. Surprisingly, chimeric mice revealed that these effects were due to Myo1e deficiency in leukocytes. Vascular permeability was not significantly altered in Myo1e KO mice. Myo1e-deficient neutrophils showed diminished arrest, spreading, uropod formation, and chemotaxis due to defective actin polymerization and integrin activation. In conclusion, Myo1e critically regulates adhesive interactions of neutrophils with the vascular endothelium and neutrophil extravasation. Myo1e may therefore be an interesting target in chronic inflammatory diseases characterized by excessive neutrophil recruitment.

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