Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo

2019 ◽  
Vol 60 (1-2) ◽  
pp. 53-62
Author(s):  
Feifei Du ◽  
Yongzhi Wang ◽  
Zhiyi Ding ◽  
Matthias W. Laschke ◽  
Henrik Thorlacius
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pharmacological Intervention ◽  
Lymphocyte Function ◽  
Microvascular Endothelium ◽  
Recruitment Methods ◽  
Leukocyte Accumulation ◽  
Tnf Α

Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.

Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation

2015 ◽  
Vol 56 (1-2) ◽  
pp. 19-31 ◽  
Author(s):  
Johanna Puegge ◽  
Yongzhi Wang ◽  
Jonas Roller ◽  
Su Zhang ◽  
Lingtao Luo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cell Damage ◽  
Leukocyte Recruitment ◽  
Pharmacological Intervention ◽  
Lymphocyte Function ◽  
Leukocyte Accumulation ◽  
Histone 3 ◽  
Neutrophil Depletion

Background: Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation. Methods: Histone 3 and TNF-α were intrascrotally administered, and anti-P-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1) antibody and neutrophil depletion antibody were injected intravenously or intraperitoneally. Results: Intrascrotal injection of histone 3 dose-dependently increased leukocyte recruitment. Neutrophil depletion abolished intravascular and extravascular leukocytes after histone 3 challenge, suggesting that neutrophils were the dominating leukocyte subtype responding to histone stimulation. Pretreatment with an anti-P-selectin and an anti-PSGL-1 antibody abolished histone-stimulated neutrophil rolling, adhesion and emigration. When the anti-P-selectin or the anti-PSGL-1 antibody was administrated after histone 3 stimulation, neutrophil rolling was reduced, whereas the number of firmly adherent and emigrated neutrophils were unchanged, suggesting that the inhibitory effect of blocking P-selectin and PSGL-1 on neutrophil adhesion and recruitment was due to the reduction in neutrophil rolling. Moreover, pretreatment with antibodies against Mac-1 and LFA-1 had no effect of neutrophil rolling but abolished adhesion and emigration evoked by histone 3. Thus, our data demonstrate that P-selectin and PSGL-1 play an important role in histone-induced inflammatory cell recruitment by mediating neutrophil rolling as a precondition for histone-provoked firm adhesion and emigration in vivo. Moreover, we conclude that both Mac-1 and LFA-1 are critical in supporting histone-provoked firm adhesion of neutrophils to endothelial cells. Conclusion: These novel findings define specific selectins and integrins as potential targets for pharmacological intervention in histone-dependent inflammatory diseases.

Role of macrophage CD44 in the disposal of inflammatory cell corpses*

2002 ◽  
Vol 103 (5) ◽  
pp. 441-449 ◽  
Author(s):  
Sharon VIVERS ◽  
Ian DRANSFIELD ◽  
Simon P. HART
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Surrounding Tissue ◽  
Human Macrophage ◽  
Neutrophil Granulocytes ◽  
Apoptotic Cells ◽  
Tissue Destruction

Understanding the cellular and molecular mechanisms that determine whether inflammation resolves or progresses to scarring and tissue destruction should lead to the development of effective therapeutic strategies for inflammatory diseases. Apoptosis of neutrophil granulocytes is an important determinant of the resolution of inflammation, providing a mechanism for down-regulation of function and triggering clearance by macrophages without inducing a pro-inflammatory response. However, if the rate of cell death by apoptosis is such that the macrophage clearance capacity is exceeded, apoptotic cells may progress to secondary necrosis, resulting in the release of harmful cellular contents and in damage to the surrounding tissue. There are many possible ways in which the rate and capacity of the macrophage-mediated clearance of apoptotic cells may be enhanced or suppressed. Ligation of human macrophage surface CD44 by bivalent monoclonal antibodies rapidly and profoundly augments the capacity of macrophages to phagocytose apoptotic neutrophils in vitro. The molecular mechanism behind this effect and its potential significance in vivo is a current focus of research.

scholarly journals CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 777-785 ◽  
Author(s):  
Stefanie Kliche ◽  
Tim Worbs ◽  
Xiaoqian Wang ◽  
Janine Degen ◽  
Irene Patzak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Lymphocyte Function ◽  
Essential Components ◽  
Antigen Presenting ◽  
Inside Out

Abstract The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.

scholarly journals HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts

2017 ◽  
Vol 95 (9) ◽  
pp. 1030-1038 ◽  
Author(s):  
Haining Zhang ◽  
Yanhua He ◽  
Guiping Zhang ◽  
Xiaobin Li ◽  
Suikai Yan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Myocardial Inflammation ◽  
Physiological Concentration ◽  
Physiological Level ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Inflammatory Action

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1β in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

scholarly journals Expression and role of ABIN1 in sepsis: In vitro and in vivo studies

Open Medicine ◽  
2020 ◽  
Vol 16 (1) ◽  
pp. 033-040
Author(s):  
Haolan Li ◽  
Aichen Sun ◽  
Taocheng Meng ◽  
Yan Zhu
Keyword(s):  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Organ Injury ◽  
In Vivo Studies ◽  
Inflammatory Factors ◽  
Septic Mouse ◽  
Raw264.7 Macrophages ◽  
Tnf Α

AbstractIn this research, we attempted to explain the effect and the related molecular mechanisms of ABIN1 in lipopolysaccharide (LPS)-induced septic mice or RAW264.7 macrophages. LPS was adopted to treat RAW264.7 macrophages for 4 h, and the levels of inflammatory factors were assessed by ELISA. Besides, ABIN1 expression was measured by quantitative reverse transcription polymerase chain reaction. Apparently, LPS enhanced immunoreaction, suggested by increased expression of IL-1β, tumor necrosis factor (TNF)-α, and IL-6. ABIN1 levels were obviously reduced compared to the control. Furthermore, we evaluated the roles of ABIN1-plasmid in immunoreaction and nuclear factor-κB (NF-κB) pathway. We found that ABIN1-plasmid significantly reduced the expression of IL-1β, TNF-α, and IL-6 in LPS-treated cells and inhibited NF-κB pathway activation. Meanwhile, a septic mouse mode was conducted to validate the role of ABIN1 in inflammatory response and organ damage in vivo. These data suggested that ABIN1-plasmid significantly inhibited the secretion of inflammatory cytokines and Cr, BUN, AST, and ALT levels in the serum of LPS-stimulated mice compared to LPS + control-plasmid group, reflecting the relieved inflammation and organ injury. In summary, the present findings indicated that ABIN1 alleviated sepsis by repressing inflammatory response through NF-κB signaling pathway, emphasizing the potential value of ABIN1 as therapeutic strategy for sepsis.

Sickle Cell Vaso-Occlusion Is Triggered by E-Selectin Ligand Signaling and Propagated by the Leukocyte Integrin Mac-1.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 145-145 ◽  
Author(s):  
Andres Hidalgo ◽  
Jungshan Chang ◽  
Anna J. Peired ◽  
Elaine Y. Chiang ◽  
Paul S. Frenette
Keyword(s):  
Sickle Cell ◽  
Intravital Microscopy ◽  
High Speed ◽  
Molecular Mechanisms ◽  
Leading Edge ◽  
Tnf Α ◽  
Selectin Ligand ◽  
Adherent Leukocytes

Abstract Vasoocclusion (VOC) is the leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Intravital microscopy studies in a murine model of SCD have revealed that capture of sickle red blood cells (RBC) by intravascular adherent leukocytes (WBC) plays an important role in VOC, and that deficiency in both P-and E-selectins protect from VOC. Here, we have investigated the cellular and molecular mechanisms leading to sickle RBCs interactions with adherent WBCs. Intravital microscopy analyses of the individual role of P- or E-selectin revealed, unexpectedly, a profound reduction in RBC-WBC interactions in Berkeley sickle mice lacking E-selectin (Sele−/−; >97% reduction), whereas the protection was only partial in the absence of endothelial P-selectin. Since E-selectin is expressed exclusively on the endothelium, and its deficiency does not alter WBC recruitment, we hypothesized that E-selectin might provide activation signals to neutrophils that allow them to capture RBCs. During our studies, we observed that RBC-WBC interactions are not exclusive of sickle animals but are also present in wild-type B6 mice treated with TNF-α, suggesting that this phenomenon accompanies a physiological inflammatory response. We found that RBC-WBC interactions in B6 mice occur at a lower frequency than in sickle mice and that these interactions are also reduced in Sele−/− mice (60% reduction; p<0.05). We thus reasoned that B6 mice might provide a convenient model to gain molecular insight into RBC-WBC interactions in vivo. Since PSGL-1, CD44 and ESL-1 harbor the entire E-selectin ligand activity on neutrophils in vivo (Hidalgo et al., Immunity 2007), we investigated which of these glycoproteins mediates the signals allowing RBC capture. High speed digital multichannel fluorescence intravital microscopy analyses revealed that RBC-WBC interactions were only markedly reduced in the absence of ESL-1 (63% reduction, p<0.001), but not in the absence of PSGL-1 or CD44. Further detailed image analyses mapped RBC captures at the leading edge of adherent neutrophils, an area where chemokine receptors and integrins may accumulate. Since selectin-mediated signaling is known to activate β2 integrins, we tested the role of Mac-1, whose expression and affinity are elevated in neutrophils from SCD patients. We found that RBC-WBC interactions were virtually absent in mice deficient in Mac-1 (97% reduction; p<0.0001). To determine whether E-selectin/ESL-1-mediated signaling promoted Mac-1 activation, we developed an assay to assess Mac-1 activity in real time on adherent WBCs in vivo. Albumin-coated fluorobeads bound to subsets of adherent leukocytes in TNF-α-stimulated venules of B6 mice. These interactions were Mac-1-dependent since they were ablated in Itgam−/− mice. Absence of E-selectin or ESL-1, but not P-selectin, PSGL-1 or CD44, significantly reduced Mac-1 activity (by 36% and 52%, respectively; p<0.05). In contrast, Mac-1 activation on adherent leukocytes was dramatically increased in inflamed venules of sickle mice (2.5-fold; p<0.001) and was restricted to a subset of adherent neutrophils. Preliminary experiments in which Mac-1 function is blocked in sickle animals with a monoclonal antibody revealed a reduction of RBC-WBC interactions (by 57%) compared to an isotype control antibody. Our results indicate that the binding of E-selectin to neutrophil ESL-1 promotes Mac-1 activation, which in turn mediates the capture of sickle RBCs. These findings provide attractive therapeutic targets to alleviate this devastating disease.

Platelet-Leukocyte Conjugation Mediated By GPIbα-αXβ2 (CD11c/CD18) Interaction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1029-1029 ◽  
Author(s):  
Edward F. Plow ◽  
Valentin P Yakubenko ◽  
Valentin Ustinov ◽  
Elzbieta Pluskota ◽  
José A López ◽  
...  
Keyword(s):  
Small Molecules ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Interaction ◽  
Intact Skin ◽  
Leukocyte Accumulation ◽  
Activated Platelets ◽  
Lesion Severity

Abstract Background The formation of platelet-leukocyte conjugates has been implicated in a variety of pathologies, including thrombosis, atherosclerosis, glomerulonephritis, multiple sclerosis and other inflammatory diseases. In prior studies (Simon et al., J. Exp Med, 2000, 193-204), platelet GPIbα and leukocyte αMβ2 (CD11b/CD18) had been implicated as receptor:counter-receptor pairing in mediating formation of platelet:leukocyte complexes. A specific segment (αM201-217) in the I domain of αM (CD11b) subunit of αMβ2 engaged GPIbα, and a peptide (M2) corresponding to this segment blocked neutrophil recognition of platelets and anti-M2 blocked conjugate formation (Ehlers et al., J. Exp. Med, 2003, 1077-88). The I-domains of αM and αX are highly conserved (74% homology), but αX has different amino acids at two positions shown to be critical for recognition of GPIbα by the αM I-domain. This study considers the role of a particular receptor:counter-receptor pairing, GPIb on platelets and αXβ2 (CD11c/CD18) on leukocytes, in mediating this heterotypic cell interaction. Methods and Results To directly address whether αXβ2 recognizes GPIbα, αXβ2 was expressed in HEK cells and its corresponding I-domain was expressed and purified. αXβ2 cells adhered specifically to GPIbα, and purified αX I-domain bound to platelets by flow cytometry and to GPIbα by surface plasmon resonance. However, this interaction was readily distinguished from that of αM I-domain binding to GPIbα. αX binding to GPIbα was not inhibited by: 1) M2 or anti-M2; 2) a peptide from a region of GPIbα implicated in vWF interaction and that blocked adhesion of αMβ2 cells to GPIbα; 3) small molecules that blocked αM I-domain binding; and 4) mutations in GPIbα that blocked αM I-domain binding. Furthermore, by mutational analyses, a region of αX I domain was implicated binding GPIbα that is structurally distant and unrelated to the αM I domain binding site. Next, we examined the role of αXβ2 in vivo in a cytokine- and neutrophil-dependent inflammatory response. The local Shwartzman-like reaction (LSR), induced by successive LPS and cytokine injections into the skin, produces a thrombo-hemorrhagic vasculitis, which depends on leukocytes and their interaction with activated platelets and endothelial cells. In prior work, we have shown that the LSR is dependent upon leukocyte αM and platelet GPIba. Leukocyte-derived microparticles promote the accumulation of fibrin, generation of occlusive thrombi, and eventual hemorrhage from inflamed blood vessels. The LSR produces hemorrhage in the intact skin 24 hours after TNF-a injection. CD11c-/- mice subjected to LSR exhibited a significant reduction in the development of hemorrhagic lesions. In analysis blinded to genotype, CD11c-/- mice had a 76% reduction in lesion severity (lesion hemorrhage score: WT, 3.4 ± 1.0, n=12 vs. CD11c-/-, 0.8 ± 1.0, n=11; P<0.001). Histopathology of vasculitic lesions demonstrated substantial reductions in erythrocyte extravasation, edema, leukocyte accumulation, and occlusive thrombi in CD11c-/- mice. Conclusions Leukocyte αXβ2 (CD11c/CD18) recognizes GPIbα on platelets in a way distinct from αMβ2 (CD11bCD18). This interaction appears to be functionally significant in vivo and could be targeted for suppressing adverse inflammatory responses. Disclosures: Simon: Cordis/J&J: Consultancy; Janssen/J&J: Consultancy; Medtronic Vascular: Consultancy; Merck: Consultancy; Medtronic Foundation: Research Funding.

Regulation of microRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
Ilangovan Ramachandran ◽  
Sneha Krishnamoorthy ◽  
Yuvaraj Sambandam ◽  
Satish Ramalingam ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Colorectal Carcinogenesis ◽  
Model Systems ◽  
Necrosis Factor Alpha ◽  
Multi Stage ◽  
Mechanistic Approach ◽  
Tnf Α ◽  
Factor Alpha

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

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