scholarly journals Pro-Inflammatory Effects of Platelet Transfusions in Newborn Mice with and without Underlying Inflammation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2146-2146
Author(s):  
Patricia E Davenport ◽  
Emily Nolton ◽  
Henry Feldman ◽  
Zhi-Jian Liu ◽  
Martha Sola-Visner
Keyword(s):  
Inflammatory Response ◽  
Conflicts Of Interest ◽  
Lethal Dose ◽  
Preterm Neonates ◽  
Genetic Syndromes ◽  
Newborn Mice ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
Underlying Inflammation ◽  
Platelet Transfusions

Abstract Platelet transfusions (PTx) are frequently given to thrombocytopenic preterm neonates at higher platelet count (PC) thresholds than those used in adults, in an attempt to reduce their bleeding risk. However, in the largest randomized trial of neonatal PTx thresholds, infants transfused at a higher PC threshold had a significantly higher mortality and/or major bleeding compared to infants transfused at a lower threshold. Since platelets carry multiple cytokines and chemokines, and since activated adult platelets may have a higher ability to interact with immune cells than neonatal platelets (due to their higher P-selectin expression levels), we hypothesized that the deleterious effects of PTx in neonates would be related to pro-inflammatory effects. We further hypothesized that the effects of PTx on the systemic inflammatory response would be different in thrombocytopenic neonates with non-inflammatory conditions (e.g., intrauterine growth restriction, drugs, genetic syndromes) compared to neonates with underlying inflammation (e.g., sepsis, necrotizing enterocolitis). To test the effects of PTx in the absence of inflammation, we transfused healthy post-natal day 10 (P10) C57BL/6 pups with washed platelets (5x10 7/g, isolated from adult C57BL/6J mice or eGFP+ mice) or with Tyrode's buffer (TY control). Blood was collected via terminal bleed 2h, 4h, and 6h after transfusion, and plasma was separated for quantification of 31 pro- and anti-inflammatory cytokines by multiplex (n=5-10 mice per group/timepoint). Two hours after PTx, the transfused mice exhibited significantly higher levels of G-CSF, IL-1, IL-1, IL-6, IL-17, KC (CXCL1) and MCP-1 compared to controls, with the most striking increases observed in IL-6 (928±19 vs. 135±36 pg/dL, p<0.001) and KC (1201±239 vs 371±77 pg/dL, p=0.001). At 4h post-transfusion, the levels of most cytokines were decreasing, with the exception of G-CSF (1940±276 vs. 825±126 pg/dL, p=0.003), MCP-1 (185±39 vs. 58±14 pg/dL, p=0.003), and IL-17 (2.12±1 vs. 0.66±0.3 pg/dL, p=0.002), which peaked at four hours. All cytokines were decreasing by 6h. Next, to model neonates with inflammatory conditions, we injected P10 pups with lipopolysaccharide (LPS) IP at a sub-lethal dose (1µg/g), which induced mild weight loss, thrombocytopenia (~ 50% drop in PC), and leukopenia followed by leukocytosis. Two hours after LPS injection, pups were transfused with washed platelets from adult C57BL/6 mice or TY (as above). Blood was obtained by terminal phlebotomy 4h, 8h or 18h post LPS injection and plasma was separated and stored for cytokine quantification by multiplex. 4h after LPS, PTx pups had significantly higher levels of leukemia inhibitory factor (LIF, a member of the IL-6 family) compared to TY controls (35±6 pg/mL vs. 17±3.9 pg/mL, p<0.01). At both 4 and 8h, IL-6 and G-CSF levels were extremely high and at or above the upper limit of the standard curve in both groups. By 18h post-LPS, the majority of cytokines had decreased to near-normal levels in TY control pups, while IL-6, IL-5, KC (CXCL1) and IL-10 remained significantly elevated in PTx mice (IL-6: 601±114 vs. 187±38 pg/mL, p=0.0007; IL-5: 659±257 vs. 486±191 pg/mL, p=0.01; KC: 4569±1370 vs. 2686±827 pg/mL, p=0.04; IL-10: 729±283 vs. 330±131 pg/mL, p=0.009). Since IL-10 is an anti-inflammatory cytokine, we also evaluated the relation of IL-6 to IL-10 in PTx vs. TY control mice. This analysis showed that IL-6 levels were 2.3 times higher for any given IL-10 level in pups who received PTx compared to controls. In conclusion, our findings suggest that platelet transfusions induce an inflammatory response in newborn mice without underlying inflammation, characterized mostly by elevations in IL-6, G-CSF and KC. In newborn pups with underlying sub-lethal inflammation, platelet transfusions seem to prolong the inflammatory response. These observations may provide an explanation for the increased morbidity and mortality in human neonates receiving liberal PTx. Studies to identify the mechanisms through which platelets induce these responses are ongoing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Severity of Thrombocytopenia at the Time of Platelet Transfusion Influences Post-Transfusion Platelet Kinetics and the Effects of Platelets on Plasma Cytokines in a Model of Murine Neonatal Sepsis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 98-98
Author(s):  
Patricia Davenport ◽  
Jorge Canas ◽  
Viola Lorenz ◽  
Zhi-Jian Liu ◽  
Chiara Badur ◽  
...  
Keyword(s):  
Neonatal Sepsis ◽  
Platelet Transfusion ◽  
Bleeding Risk ◽  
Tnf Alpha ◽  
Preterm Neonates ◽  
Laboratory Equipment ◽  
Newborn Mice ◽  
Plasma Cytokines ◽  
Anti Inflammatory ◽  
Platelet Transfusions

Thrombocytopenia affects 20-30% of neonates admitted to the Neonatal Intensive Care Unit (NICU) and up to 70% of those born extremely prematurely, with sepsis being one of the most frequent causes. Since preterm neonates also have a high bleeding risk, it has been widely accepted that they should receive platelet transfusions at higher platelet count (PC) thresholds than older children or adults. However, there is no consensus regarding what the appropriate threshold should be, particularly in critically ill infants. Surveys and observational studies have revealed extraordinary world-wide variability in neonatal platelet transfusion thresholds, with North-American neonatologists typically using more liberal thresholds (i.e. PC<100x109/L) than European neonatologists. Here we hypothesized that the severity of thrombocytopenia at the time of platelet transfusion would influence the post-transfusion platelet kinetics and the effects of platelets on the inflammatory response of septic newborn mice. To test these hypotheses, we used a validated model of neonatal sepsis/peritonitis, consisting of injecting cecal slurry (CS) or 15% glycerol (control) IP into post-natal day 10 (P10) mice. The CS dose used in these studies induced severe sepsis with a high mortality. c-MPL KO pups (which lack the TPO receptor, pre-infection PC 92±38 x 103/µL) and WT B6 pups (pre-infection PC 748±169 x 103/µL) were used to model severe and mild thrombocytopenia at the time of transfusion, respectively. Two hours after infection, mice from both genotypes were transfused with washed platelets from adult GFP mice (5x107platelets/gram) or with Tyrode's buffer. PCs and GFP% were measured by flow cytometry 2 and 22 hrs post-transfusion. At 2 hours, as expected, transfused septic mice of both genotypes had higher PCs than non-transfused septic littermates (217±118 vs 24±9 x103/µL for c-MPLKO mice, p<0.0001, and 764±193 vs. 549±155 x103/µL for WT mice, p<0.01). By 22 hours post-transfusion, transfused septic c-MPL KO mice still had significantly higher PCs than their non-transfused septic littermates (127±71 vs. 21±12 x103/µL, p<0.01; n=7 per group), but there were no significant differences between transfused and non-transfused septic WT mice (415±139 vs. 310±113 x 103/µL, p=0.1;n=7 per group). Between 2 and 22 hrs post-transfusion, PCs dropped at a nearly three-fold higher rate in transfused septic WT mice than in transfused septic c-MPL KO mice (by 17±8 vs. 6±5 x103 platelets/µL/h). In that interval, adult transfused platelets (GFP+) decreased by a larger percentage than neonatal platelets (GFP-) in transfused septic mice of both genotypes (by 64±14% vs. 46±21% in WT mice, and by 53±27% vs. 28±28% in c-MPL KO mice, both p<0.01), although these observations don't account for ongoing neonatal platelet production. Examination of a panel of plasma cytokines 24h after infection revealed significantly increased levels of pro-inflammatory (IL-6, TNF-alpha, and MCP-1) and anti-inflammatory (IL-10) cytokines in non-transfused septic neonates of both genotypes, compared to controls. Interestingly, platelet transfusions significantly reduced the levels of these cytokines in septic WT mice compared to non-transfused littermates, but had no effect on the cytokine levels of septic c-MPLKO mice. Platelets have been recently shown to reduce TNF-alpha production by murine macrophages at high LPS concentrations (Xiang, 2013) and to sequester both pro- and anti-inflammatory cytokines released by monocytes in response to LPS (Carestia, 2019). Our findings suggest that, in neonatal sepsis, this might require PCs to be above a certain threshold. The consequences of these differences on the outcomes of neonatal sepsis are being investigated. Disclosures Stowell: Grifols: Honoraria. Sola-Visner:Sysmex America, Inc.: Other: Laboratory equipment on loan, Research Funding.

Developmental Differences Between Newborn and Adult Mice In Response To Romiplostim

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3542-3542 ◽  
Author(s):  
Katherine A Sparger ◽  
Nan Li ◽  
Zhi-Jian Liu ◽  
Haley Ramsey ◽  
Martha Sola-Visner
Keyword(s):  
Conflicts Of Interest ◽  
Fold Increase ◽  
Developmental Differences ◽  
Growth Potential ◽  
Preterm Neonates ◽  
Newborn Mice ◽  
Adult Mice ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract Thrombocytopenia affects 20-35% of infants admitted to Neonatal Intensive Care Units. The incidence of thrombocytopenia is inversely proportional to gestational age, and approaches 70% among the most preterm neonates (birth weight <1,000 grams). Preterm infants also have the highest incidence of bleeding of any age group, with 25-31% developing intracranial hemorrhage. Currently, platelet (plt) transfusions are the only therapeutic option for thrombocytopenic neonates. In the last 5 years, two thrombopoietin (TPO) mimetics, romiplostim (ROM) and eltrombopag, received FDA approval for the treatment of adults with ITP. Based on the severity and duration of thrombocytopenia, 10% of thrombocytopenic neonates could benefit from TPO-mimetic therapy. Our prior in vitro studies demonstrated that human neonatal megakaryocyte (MK) progenitors are significantly more sensitive to TPO than adult progenitors (Pastos et al., Blood, 2006; Liu et al., Blood, 2011). This study was designed to compare the in vivo responses of newborn vs. adult mice to ROM. Based on prior observations, we hypothesized that newborn pups would be more sensitive to TPO-mimetics than adult mice. As a first step, healthy adult C57BL/6 mice were given a single subcutaneous (SC) injection of 0.1% BSA (control) or ROM at a dose of 10, 30, 100, or 300 ng/g body weight. Newborn mice on post-natal day 1 (P1) received a single SC injection of either 0.1% BSA or ROM at a dose of 30 or 300 ng/g. Plt count and immature plt fraction (IPF) were measured on the day of injection and every other day for 14 days. The baseline plt count in adult mice was 1,184±204 x103/µL. Adult mice treated with ROM (n=3-4 per group) exhibited a dose-dependent increase in plt count and IPF, which peaked on day 5 in those receiving lower ROM doses (10 and 30 ng/g), and on day 7 in those receiving higher ROM doses (100 and 300 ng/g). On day 7, adult mice treated with ROM 300 ng/g had a 4.2-fold increase in plt count compared to BSA controls (6,733±511 vs. 1,600±216 x103/µL, respectively; p<0.0001). Newborn mice (P1) had significantly lower baseline plt counts (624±130 x103/µL; p<0.0001) compared to adults, and similarly responded to ROM injection with a dose-dependent increase in plt count that peaked on day 5. However, plt counts on post-natal day 5 (P5) were 1,020±198 x103/µL for newborn mice treated with ROM 30 ng/g and 1,355±137 x103/µL for newborn mice treated with ROM 300 ng/g (n=17 per group), representing less than a 2-fold increase over BSA treated pups (701±119 x103/µL). To evaluate the effect of ROM on megakaryopoiesis, a subset of adult and newborn mice treated with 0.1% BSA or ROM 300 ng/g (n=3-4 per group) were euthanized on day 5 after injection. Liver, spleen, and bone marrow (BM) MKs were immunohistochemically stained for von Willebrand factor and quantified as described (Hu Z et al., Neonatology, 2010). Overall, ROM-treated adult mice had significantly increased numbers of MKs compared to controls in BM (2.3-fold increase; p=0.0002) and spleen (3.9-fold increase; p=0.006). ROM-treated newborn mice exhibited non-significant increases in MK numbers in BM (2.2-fold increase; p=0.19), spleen (1.6-fold increase; p=0.35), and liver (1.4-fold increase; p=0.31). Because newborn C57BL/6 mice transition from fetal liver to adult BM hematopoiesis during the first 10 to 14 days of life and the BM is not well formed until P10, we injected newborn mice at P5 (instead of P1) and evaluated the response to ROM. Similar to the younger group, P5 mice treated with ROM 300 ng/g reached peak platelet counts at P11, but the plt count was only 1.4-fold higher than BSA control animals (1,340±440 vs. 927±151 x103/µL, respectively; p=0.19). In conclusion, this study indicated that newborn mice are less responsive to ROM than adult mice. This was a surprising finding, given that human neonatal MK progenitors have been consistently shown to be more sensitive to TPO than adult MK progenitors. The reasons underlying the modest in vivo response of neonates are unclear, but might be related to the transition in hematopoietic sites that occurs during this period in murine development (corresponding to the second trimester of human gestation), high baseline thrombopoietic demands associated with rapid growth, potential pharmacokinetic factors, or developmental differences in the splenic or BM microenvironments of newborn and adult mice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The potential roles of m6A modification in regulating the inflammatory response in microglia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Qi Li ◽  
Shaohong Wen ◽  
Weizhen Ye ◽  
Shunying Zhao ◽  
Xiangrong Liu
Keyword(s):  
Inflammatory Response ◽  
Pathway Analysis ◽  
Cellular Processes ◽  
Qrt Pcr ◽  
Inflammatory Conditions ◽  
Functional Implications ◽  
Genetic Information Processing ◽  
Anti Inflammatory ◽  
Microarray Analyses ◽  
The Brain

Abstract Background Microglia are key regulators of the inflammatory response in the brain. Adenosine in RNAs can be converted to m6A (N6-methyladenosine), which regulates RNA metabolism and functions as a key epitranscriptomic modification. The m6A modification pattern and m6A-related signatures under pro-inflammatory and anti-inflammatory conditions of microglia remain unclear. Methods Primary rat microglia were differentiated into pro-inflammatory M1-like (M1-L), anti-inflammatory M2-like (M2-L), and resting, unstimulated (M0-L) phenotypes. m6A mRNA and lncRNA epitranscriptomic microarray analyses were performed, and pathway analysis was conducted to understand the functional implications of m6A methylation in mRNAs and lncRNAs. The m6A methylation level and gene expression of mRNAs and lncRNAs were subsequently verified by m6A Me-RIP and qRT-PCR. Results A total of 1588 mRNAs and 340 lncRNAs, 315 mRNAs and 38 lncRNAs, and 521 mRNAs and 244 lncRNAs were differentially m6A methylated between M1-L and M0-L (M1-L/M0-L), M2-L and M0-L (M2-L/M0-L), M2-L and M1-L (M2-L/M1-L), respectively. Furthermore, 4902 mRNAs, 4676 mRNAs, and 5095 mRNAs were identified distinctively expressed in M1-L/M0-L, M2-L/M0-L, and M2-L/M1-L, respectively. Pathway analysis of differentially m6A methylated mRNAs and lncRNAs in M1-L/M0-L identified immune system, signal transduction, and protein degradation processes. In contrast, the distinct m6A methylated mRNAs in M2-L/M0-L were involved in genetic information processing, metabolism, cellular processes, and neurodegenerative disease-related pathways. We validated m6A methylation and the expression levels of five mRNAs and five lncRNAs, which were involved in upregulated pathways in M1-L/M0-L, and five mRNAs involved in upregulated pathways in M2-L/M0-L. Conclusions These findings identify a distinct m6A epitranscriptome in microglia, and which may serve as novel and useful regulator during pro-inflammatory and anti-inflammatory response of microglia.

scholarly journals Platelet Transfusions Can Increase or Decrease the Inflammatory Response and Mortality in a Murine Model of Neonatal Polymicrobial Sepsis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
Patricia E Davenport ◽  
Hsuan-Hao Fan ◽  
Emily Nolton ◽  
Henry Feldman ◽  
Viola Lorenz ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Murine Model ◽  
Neonatal Sepsis ◽  
Statistical Significance ◽  
Bacterial Species ◽  
Polymicrobial Sepsis ◽  
Preterm Neonates ◽  
Significant Difference ◽  
Buffer Control ◽  
Platelet Transfusions

Abstract Thrombocytopenia affects 18-35% of all neonates in the Neonatal Intensive Care Unit and ~70% of those born extremely prematurely, with sepsis being a frequent cause. Platelet transfusions (PTx) are frequently given to septic preterm neonates at higher platelet count (PC) thresholds than those used in adults, in an attempt to reduce their bleeding risk. However, in the largest randomized trial of neonatal PTx thresholds, infants transfused at a higher PC threshold had a significantly higher mortality and/or major bleeding compared to infants transfused at a lower threshold. We hypothesized that the deleterious effects of PTx would be related to a potential "developmental mismatch" resulting from adult platelets being transfused into a neonate. Among other developmental differences, adult platelets (human and murine) exhibit significantly higher surface P-selectin expression following activation than neonatal platelets. P-selectin is essential for the interaction of platelets with immune cells. Thus, we hypothesized that adult platelets transfused into septic neonates would be consumed faster than endogenous neonatal platelets (due to higher potential for immune interaction), and would increase inflammation and mortality. To test these hypotheses, we used a published murine model of neonatal sepsis, consisting of injecting cecal slurry (CS) into C57BL/6 pups. CS batches were prepared by isolating the cecal content of adult C57BL/6 mice, which was weighted, aliquoted and frozen until use. Three different CS batches were prepared and injected IP into post-natal day 10 pups at a dose of 1.1 (CS1) or 1.0 mg/g (CS2 and 3). Two hours after infection, pups were transfused with washed platelets from adult GFP mice (5x10 7 platelets/g) or Tyrode's buffer (control). Weights, PCs and GFP platelet % were measured before, 4h and 24h post-infection. Blood was collected via terminal bleed at 24h, and plasma separated for quantification of 31 cytokines by multiplex. Despite identical preparation, CS batches varied greatly in their 24h mortality (11% vs 73% vs. 30% for CS1, 2 and 3, respectively). Moreover, PTx had different effects on the mortality of pups infected with different CS batches, increasing the 24h mortality of pups infected with CS1 (30% in transfused vs 11% in non-transfused, RR 2.70, 95% CI 1.02-7.15) but decreasing the mortality of pups infected with CS2 (46% vs. 73%) or CS3 (9% vs. 30%), with a combined RR of 0.52; 95% CI 0.30-0.91. Bacterial counts differed between CS batches, but did not correlate with mortality. Comparison of the microbiome composition using deep sequencing revealed an increased presence of pathogenic bacterial species (Legionella, Sutterella, and Helicobacter species) in CS2 and 3 compared to CS1, and a relative abundance of beneficial bacterial (Actinobacteria and Proteobacteria) in CS1. Different CS batches also elicited different cytokine responses, with significant differences noted in G-CSF, IL-1α, IL-1β, IL-3, IL-7, IL-12p70, and IL-15 levels (p&lt;0.05). For all of these cytokines, except G-CSF, levels were lower in mice infected with CS1 compared to CS2 or 3. Next, we investigated the effects of PTx on the plasma cytokine profile of mice infected with CS1 or CS2/3 (combined), compared to their infected, non-transfused littermates. For nearly all cytokines, PTx increased the response after infection with CS1, but decreased it after infection with CS2/3, with a significant difference in mean global cytokine effect (p&lt;0.0001). For individual cytokines, however, these differences only reached statistical significance for LIX (CXCL5, p=0.04) and approached significance for IL15 and IL17 (p=0.06). Finally, we developed a mathematical model to compare the consumption of endogenous neonatal platelets (GFP-) to that of transfused adult platelets (GFP+) in pups infected with CS1 vs. CS2. In both, the calculated percent consumption was higher for adult platelets than for neonatal platelets (54.8% vs. 32.6% for CS1 and 56.5% vs. 40.4% for CS2). In conclusion, our findings support the hypothesis that adult transfused platelets are consumed faster than endogenous platelets in early neonatal sepsis, and demonstrate that platelet transfusions can either enhance or attenuate the neonatal inflammatory response and the mortality in a model of murine polymicrobial sepsis, depending on the bacterial composition of the inoculum and/or the severity of the sepsis. Disclosures Stowell: Grifols: Speakers Bureau; Argenx: Speakers Bureau; Alexion: Consultancy.

scholarly journals Beneficial Dysregulation of the Time Course of Inflammatory Mediators in Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Factor-Deficient Mice

2010 ◽  
Vol 17 (5) ◽  
pp. 699-704 ◽  
Author(s):  
Sreedevi Srinivasan ◽  
Susan E. Leeman ◽  
Salomon Amar
Keyword(s):  
Tumor Necrosis Factor ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Tumor Necrosis ◽  
Time Course ◽  
Lethal Dose ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT To begin to understand the surprising survival of macrophage-specific lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient (macLITAF−/−) animals after a lethal dose of lipopolysaccharide (LPS), as reported earlier, the present follow-up study focuses on the role of LITAF in the regulation of inflammatory cytokines secreted in response to lethal or sublethal doses of LPS administered to wild-type (WT) and macLITAF−/− mice. A time course study of kinase expression in peritoneal macrophages revealed increased phosphorylation of prosurvival kinases Akt, Erk1/2, and ribosomal S6 kinase (RSK) in macLITAF−/− mice compared to that in WT mice (n = 8), confirming their role in LPS-mediated diseases. macLITAF−/− mice (n = 8) survived a lethal dose of LPS plus d-galactosamine (d-GalN), expressing lower serum levels of pro- and anti-inflammatory cytokines than the WT levels. To extend our knowledge on LPS-induced inflammatory events, an effective sublethal dose of LPS was administered to the animals (n = 14). WT animals exhibited an acute inflammatory response that decreased after 4 h. Interestingly, macLITAF−/− mice exhibited an initial delay in the secretion of proinflammatory cytokines that peaked after 8 h and reached WT levels after 18 h. Anti-inflammatory cytokine secretions were initially delayed but increased after 4 h and remained elevated compared to WT levels, even after 18 h. Our results demonstrate that LITAF deficiency in vivo affects cytokines other than TNF-α and influences the balance between the pro- and anti-inflammatory cytokines, which protects the animals from the deleterious effects of an LPS-induced inflammatory response, resulting in a beneficial host regulation of inflammatory cytokines and in enhanced survival. Therapeutic intervention aimed at reducing LITAF via kinase modulators may prove useful in preventing LPS-induced mortality.

scholarly journals Keratinocyte and Fibroblast Wound Healing In Vitro Is Repressed by Non-Optimal Conditions but the Reparative Potential Can Be Improved by Water-Filtered Infrared A

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1802
Author(s):  
Cornelia Wiegand ◽  
Uta-Christina Hipler ◽  
Peter Elsner ◽  
Jörg Tittelbach
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Inflammatory Response ◽  
Chronic Wounds ◽  
Cytokine Gene Expression ◽  
Optimal Conditions ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
Improve Wound Healing

It is a general goal to improve wound healing, especially of chronic wounds. As light therapy has gained increasing attention, the positive influence on healing progression of water-filtered infrared A (wIRA), a special form of thermal radiation, has been investigated and compared to the detrimental effects of UV-B irradiation on wound closure in vitro. Models of keratinocyte and fibroblast scratches help to elucidate effects on epithelial and dermal healing. This study further used the simulation of non-optimal settings such as S. aureus infection, chronic inflammation, and anti-inflammatory conditions to determine how these affect scratch wound progression and whether wIRA treatment can improve healing. Gene expression analysis for cytokines (IL1A, IL6, CXCL8), growth (TGFB1, PDGFC) and transcription factors (NFKB1, TP53), heat shock proteins (HSP90AA1, HSPA1A, HSPD1), keratinocyte desmogleins (DSG1, DSG3), and fibroblast collagen (COL1A1, COL3A1) was performed. Keratinocyte and fibroblast wound healing under non-optimal conditions was found to be distinctly reduced in vitro. wIRA treatment could counteract the inflammatory response in infected keratinocytes as well as under chronic inflammatory conditions by decreasing pro-inflammatory cytokine gene expression and improve wound healing. In contrast, in the anti-inflammatory setting, wIRA radiation could re-initiate the acute inflammatory response necessary after injury to stimulate the regenerative processes and advance scratch closure.

scholarly journals Deletion of Cdk5 in Macrophages Ameliorates Anti-Inflammatory Response during Endotoxemia through Induction of C-Maf and Il-10

2021 ◽  
Vol 22 (17) ◽  
pp. 9648
Author(s):  
Pauline Pfänder ◽  
Ann-Kathrin Eiers ◽  
Ute Burret ◽  
Sabine Vettorazzi
Keyword(s):  
Inflammatory Response ◽  
Interleukin 10 ◽  
Cyclin Dependent Kinase ◽  
Inflammatory Conditions ◽  
Primary Bone ◽  
Anti Inflammatory ◽  
Factor C ◽  
Cyclin Dependent Kinase 5

Immune response control is critical as excessive cytokine production can be detrimental and damage the host. Interleukin-10 (Il-10), an anti-inflammatory cytokine produced primarily by macrophages, is a key regulator that counteracts and controls excessive inflammatory response. Il-10 expression is regulated through the transcription factor c-Maf. Another regulator of Il-10 production is p35, an activator of the cyclin-dependent kinase 5 (Cdk5), which decreases Il-10 production in macrophages, thus increasing inflammation. However, Cdk5 regulation of c-Maf and the involvement of Il-10 production in macrophages has not yet been investigated. We used in vitro primary bone marrow-derived macrophages (BMDMs) lacking Cdk5, stimulated them with lipopolysaccharid (LPS) and observed increased levels of c-Maf and Il-10. In an in vivo mouse model of LPS-induced endotoxemia, mice lacking Cdk5 in macrophages showed increased levels of c-Maf and elevated levels of Il-10 in lungs as well as in plasma, resulting in ameliorated survival. Taken together, we identified Cdk5 as a potential novel regulator of Il-10 production through c-Maf in macrophages under inflammatory conditions. Our results suggest that inhibition of Cdk5 enhances the c-Maf-Il-10 axis and thus potentiates improvement of anti-inflammatory therapy.

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