human monocytes
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2022 ◽  
Vol 12 ◽  
Author(s):  
Kathryn W. Juchem ◽  
Anshu P. Gounder ◽  
Jian Ping Gao ◽  
Elise Seccareccia ◽  
Narayana Yeddula ◽  
...  

NFAT activating protein with ITAM motif 1 (NFAM1) is an ITAM bearing-transmembrane receptor that has been reported to play a role in B cell signaling and development. We performed expression analysis of NFAM1 using publicly available gene expression data sets and found that NFAM1 expression is significantly induced in intestinal biopsies from Crohn’s disease (CD) and ulcerative colitis (UC) patients. At the cellular level, we further observed high expression of NFAM1 in monocytes and neutrophils, and low expression in B and T cells. To explore the role of NFAM1 in multiple immune cells and its potential role in IBD, we generated NFAM1-/- mice. In contrast with previous reports using NFAM1-transgenic mice, NFAM1-/- mice have no obvious defects in immune cell development, or B cell responses. Interestingly, NFAM1-/- monocytes produce reduced levels of TNF-α in response to activation by multiple IBD-relevant stimuli, including CD40L, TLR ligands and MDP. Additional cytokines and chemokines such as IL-6, IL-12, CCL3 and CCL4 are also reduced in CD40L stimulated NFAM1-/- monocytes. Collectively, these findings indicate that NFAM1 promotes monocyte activation, thereby amplifying the response to diverse stimuli. Similarly, we observed that deletion of NFAM1 in human monocytes reduces expression of CD40L-induced CCL4. Lastly, to assess the role of NFAM1 in IBD, we compared development of anti-CD40 induced colitis in NFAM1+/+ and NFAM1-/- mice. We found that although NFAM1 deletion had no impact on development of gut pathology, we did observe a decrease in serum TNF-α, confirming that NFAM1 promotes pro-inflammatory cytokine production in vivo. Taken together, we conclude that NFAM1 functions to amplify cytokine production and should be further evaluated as a therapeutic target for treatment of autoimmune disease.


2022 ◽  
Vol 23 (2) ◽  
pp. 681
Author(s):  
Sara Touhami ◽  
Fanny Béguier ◽  
Tianxiang Yang ◽  
Sébastien Augustin ◽  
Christophe Roubeix ◽  
...  

Hypoxia is potentially one of the essential triggers in the pathogenesis of wet age-related macular degeneration (wetAMD), characterized by choroidal neovascularization (CNV) which is driven by the accumulation of subretinal mononuclear phagocytes (MP) that include monocyte-derived cells. Here we show that systemic hypoxia (10% O2) increased subretinal MP infiltration and inhibited inflammation resolution after laser-induced subretinal injury in vivo. Accordingly, hypoxic (2% O2) human monocytes (Mo) resisted elimination by RPE cells in co-culture. In Mos from hypoxic mice, Thrombospondin 1 mRNA (Thbs1) was most downregulated compared to normoxic animals and hypoxia repressed Thbs-1 expression in human monocytes in vitro. Hypoxic ambient air inhibited MP clearance during the resolution phase of laser-injury in wildtype animals, but had no effect on the exaggerated subretinal MP infiltration observed in normoxic Thbs1−/−-mice. Recombinant Thrombospondin 1 protein (TSP-1) completely reversed the pathogenic effect of hypoxia in Thbs1−/−-mice, and accelerated inflammation resolution and inhibited CNV in wildtype mice. Together, our results demonstrate that systemic hypoxia disturbs TSP-1-dependent subretinal immune suppression and promotes pathogenic subretinal inflammation and can be therapeutically countered by local recombinant TSP-1.


Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 397
Author(s):  
Alexander Hedbrant ◽  
Ingrid Persson ◽  
Ann Erlandsson ◽  
Jonny Wijkander

The formation of prostaglandin E2 (PGE2) is associated with adverse inflammatory effects. However, long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) comes with risk of severe side effects. Therefore, alternative ways to inhibit PGE2 are warranted. We have investigated the effects of tea extracts and the polyphenols epigallocatechin gallate (EGCG) and quercetin on PGE2 formation, determined by immunoassay, and protein expression, determined by immunoblotting, of cytosolic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) in human monocytes. Green and black tea extracts, and with a lower potency, Rooibos tea extract, inhibited lipopolysaccharide (LPS) and calcium ionophore-induced PGE2 formation. In addition, all tea extracts inhibited the LPS-induced expression of mPGES-1, and the green and black tea extracts also inhibited, to a lesser extent, COX-2 expression. The tea extracts only marginally reduced cPLA2 expression and had no effect on COX-1 expression. EGCG, present in green and black tea, and quercetin, present in all three teas, also inhibited PGE2 formation and expression of mPGES-1, COX-2 and cPLA2. Cell-based and cell-free assays were also performed to evaluate direct effects on the enzymatic activity of COX and PGE synthases. Mainly, the cell-free assay demonstrated partial inhibition by the tea extracts and polyphenols. However, the inhibition required higher doses compared to the effects demonstrated on protein expression. In conclusion, green and black tea, and to a lesser extent Rooibos tea, are potent inhibitors of PGE2 formation in human monocytes, and mediate their effects by inhibiting the expression of the enzymes responsible for PGE2 formation, especially mPGES-1.


2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Anna Czapka ◽  
Christian Grune ◽  
Patrick Schädel ◽  
Vivien Bachmann ◽  
Karl Scheuer ◽  
...  

Abstract Background Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development. One example of such problematic molecules is 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. 6BIGOE potently modulates the release of inflammatory cytokines and lipid mediators from isolated human monocytes through inhibition of glycogen synthase kinase-3 in a favorable fashion. However, 6BIGOE suffers from poor solubility and short half-lives in biological aqueous environment and exerts cytotoxic effects in various mammalian cells. In order to overcome the poor water solubility, instability and cytotoxicity of 6BIGOE, we applied encapsulation into poly(d,l-lactide-co-glycolide) (PLGA)-based nanoparticles by employing formulation methods using the sustainable solvents Cyrene™ or 400 g/mol poly(ethylene glycol) as suitable technology for efficient drug delivery of 6BIGOE. Results For all preparation techniques the physicochemical characterization of 6BIGOE-loaded nanoparticles revealed comparable crystallinity, sizes of about 230 nm with low polydispersity, negative zeta potentials around − 15 to − 25 mV, and biphasic release profiles over up to 24 h. Nanoparticles with improved cellular uptake and the ability to mask cytotoxic effects of 6BIGOE were obtained as shown in human monocytes over 48 h as well as in a shell-less hen’s egg model. Intriguingly, encapsulation into these nanoparticles fully retains the anti-inflammatory properties of 6BIGOE, that is, favorable modulation of the release of inflammation-relevant cytokines and lipid mediators from human monocytes. Conclusions Our formulation method of PLGA-based nanoparticles by applying sustainable, non-toxic solvents is a feasible nanotechnology that circumvents the poor bioavailability and biocompatibility of the cargo 6BIGOE. This technology yields favorable drug delivery systems for efficient interference with inflammatory processes, with improved pharmacotherapeutic potential. Graphical Abstract


Author(s):  
Bruno de Jesús Arellano-Cruz ◽  
María de los Ángeles Vázquez-Prieto ◽  
Nilda Belén Fernández-Eufrasio ◽  
Dvorak Montiel-Condado ◽  
Genaro Patiño-López ◽  
...  

2021 ◽  
Vol 53 ◽  
pp. S505
Author(s):  
S. Schillo ◽  
C. Schiweck ◽  
M. Aichholzer ◽  
A. Yotova ◽  
T. Tsengenbayar ◽  
...  
Keyword(s):  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Clément Adam ◽  
Léa Paolini ◽  
Naïg Gueguen ◽  
Guillaume Mabilleau ◽  
Laurence Preisser ◽  
...  

AbstractLactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.


Biologics ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 396-415
Author(s):  
Narges Dargahi ◽  
Joshua C. Johnson ◽  
Vasso Apostolopoulos

Ingesting probiotics contributes to the development of a healthy microflora in the GIT with established benefits to human health. Some of these beneficial effects may be through the modulation of the immune system. In addition, probiotics have become more common in the treatment of many inflammatory and immune disorders. Here, we demonstrate a range of immune modulating effects of Streptococcus thermophilus by human monocytes, including decreased mRNA expression of IL-1R, IL-18, IFNαR1, IFNγR1, CCL2, CCR5, TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-8, CD14, CD86, CD4, ITGAM, LYZ, TYK2, IFNR1, IRAK-1, NOD2, MYD88, SLC11A1, and increased expression of IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-23, IFNγ, TNFα, CSF-2. The routine administration of Streptococcus thermophilus in fermented dairy products and their consumption may be beneficial to the treatment/management of inflammatory and autoimmune diseases.


2021 ◽  
Author(s):  
Priya Kulkarni ◽  
Abhay Harsulkar ◽  
Anne-Grete Martson ◽  
Siim Suutre ◽  
Aare Martson ◽  
...  

Osteophytes are a prominent feature of osteoarthritis (OA) pathology. RNA-seq of osteophytes revealed patterns corresponding to active ECM re-modulation and participation of mast cells. The cells recruitment and their activity status were confirmed by anti-TPSAB1 and anti-FC epsilon RI antibodies in immunohistochemistry. Besides subchondral bone, which is a logical yet unproven route for the cells deployment into osteophytes, the authors propose that OA synovial fluid (SF) is necessary and sufficient for maturation of mast cell precursors (MCPs) in this channel. The authors present evidences to support their claim in the form of IHC, proteomics analysis of SF samples and in vitro cell differentiation assay, wherein human monocytes (ThP1) and hematopoietic stem cells (HSCs) showed differentiation in HLA-DR+/CD206+ and FCERI+ phenotype respectively after 9 days of SF treatment. These observations expound osteophytes and resident mast cells as yet unexplained functional epicenter in OA pathology.


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