Morphology matters in immune cell chemotaxis: membrane asymmetry affects amplification

Abstract Improved understanding of the molecular mechanisms underlying ascending equine placentitis holds the potential for the development of new diagnostic tools and therapies to forestall placentitis-induced preterm labor. The current study characterized the equine placental transcriptome (chorioallantois [CA] and endometrium [EN]) during placentitis (placentitis group, n = 6) in comparison to gestationally-matched controls (control group, n = 6). Transcriptome analysis identified 2953 and 805 differentially expressed genes in CA and EN during placentitis, respectively. Upstream regulator analysis revealed the central role of toll-like receptors (TLRs) in triggering the inflammatory signaling, and consequent immune-cell chemotaxis. Placentitis was associated with the upregulation of matrix metalloproteinase (MMP1, MMP2, and MMP9) and apoptosis-related genes such as caspases (CASP3, CASP4, and CASP7) in CA. Also, placentitis was associated with downregulation of transcripts coding for proteins essential for placental steroidogenesis (SRD5A1 and AKR1C1), progestin signaling (PGRMC1 and PXR) angiogenesis (VEGFA, VEGFR2, and VEGFR3), and nutrient transport (GLUT12 and SLC1A4), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could explain placental insufficiency during placentitis. Placentitis was also associated with aberrant expression of several placenta-regulatory genes, such as PLAC8, PAPPA, LGALS1, ABCG2, GCM1, and TEPP, which could negatively affect placental functions. In conclusion, our findings revealed for the first time the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during equine placentitis, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

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Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner

Science Translational Medicine ◽

10.1126/scitranslmed.aas9292 ◽

2019 ◽

Vol 11 (511) ◽

pp. eaas9292 ◽

Cited By ~ 21

Author(s):

Bojan Shutinoski ◽

Mansoureh Hakimi ◽

Irene E. Harmsen ◽

Michaela Lunn ◽

Juliana Rocha ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Immune Cell ◽

Newborn Mouse ◽

Dependent Manner ◽

Microbial Infection ◽

Adult Mice ◽

Microbial Infections ◽

Mutant Lrrk2 ◽

Cell Chemotaxis

Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson’s disease, leprosy, and Crohn’s disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways. First, adult mice were intravenously inoculated with Salmonella typhimurium, resulting in sepsis. Second, newborn mouse pups were intranasally infected with reovirus (serotype 3 Dearing), which induced encephalitis. In both mouse models, wild-type Lrrk2 expression was protective and showed a sex effect, with female Lrrk2-deficient animals not controlling infection as well as males. Mice expressing Lrrk2 carrying the Parkinson’s disease–linked p.G2019S mutation controlled infection better, with reduced bacterial growth and longer animal survival during sepsis. This gain-of-function effect conferred by the p.G2019S mutation was mediated by myeloid cells and was abolished in animals expressing a kinase-dead Lrrk2 variant, p.D1994S. Mouse pups with reovirus-induced encephalitis that expressed the p.G2019S Lrrk2 mutation showed increased mortality despite lower viral titers. The p.G2019S mutant Lrrk2 augmented immune cell chemotaxis and generated more reactive oxygen species during virulent infection. Reovirus-infected brains from mice expressing the p.G2019S mutant Lrrk2 contained higher concentrations of α-synuclein. Animals expressing one or two p.D1994S Lrrk2 alleles showed lower mortality from reovirus-induced encephalitis. Thus, Lrrk2 alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.

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3389 Coagulation Factor Xll-mediated contact system and its role in adaptive and innate immune cell movement

Journal of Clinical and Translational Science ◽

10.1017/cts.2019.16 ◽

2019 ◽

Vol 3 (s1) ◽

pp. 5-6

Author(s):

Emily Beltran ◽

Tukisa Smith ◽

Beth Graczyk ◽

Jan Breslow ◽

Manish Ponda

Keyword(s):

Septic Shock ◽

Body Temperature ◽

Disease Severity ◽

Immune Cell ◽

Core Body Temperature ◽

Immune Mediated ◽

Eae Model ◽

Lymphoid Structures ◽

Core Body ◽

Cell Chemotaxis

OBJECTIVES/SPECIFIC AIMS: The objectives of this study are to 1) expand upon the paradigm of HK-D5 accelerated immune cell chemotaxis; 2) characterize the role of FXII in murine models of immune-mediated disease using FXII KO mice and a small molecule inhibitor of FXIIa. METHODS/STUDY POPULATION: To test whether the addition of HK-D5 peptide would accelerate C-C chemokine receptor type 2 (CCR2)-mediated chemotaxis in vitro, a real-time transwell chemotaxis assay was developed utilizing human THP-1 monocyte cell line (Fig 1). For in vivo studies, both pharmacologic FXIIa antagonism and FXll KO mice were used. Genotyping, histopathological review, FXll protein expression, and active partial thromboplastin time (aPTT) measurements were used to phenotypically characterize FXII KO mice compared to C57BL/6 wild type mice (Fig 2). Subsequently, the FXll KO mice were studied in varied models of immune-mediated disease, including LPS-induced sepsis and experimental autoimmune encephalitis (EAE), to see if and how the absence of FXll can mitigate disease severity. The EAE model involved active immunization with myelin oligodendrocyte glycoprotein (MOG) and measurement of established clinical disease severity scores. The LPS sepsis model involved an intraperitoneal injection of LPS followed by 48-hour monitoring of core body temperature using subdermal temperature transponders as a proxy for inflammatory events related to septic shock (Fig 3). RESULTS/ANTICIPATED RESULTS: HK-D5 significantly accelerates CCR2-mediated chemotaxis compared to chemokine alone (p = 0.001) similar to HK-D5’s ability to accelerate CCR7-mediated chemotaxis as previously established. The FXll KO mice were backcrossed to the C57BL/6J background and confirmed by genotyping and complete absence of FXII protein in plasma. Compared to the control, FXII KO mice have a significantly prolonged aPTT without evidence of bleeding abnormalities, which confirms the expected phenotype previously described and recapitulates what is observed in Factor XII deficiency in humans. KO mice showed no significant gross or histopathological differences in secondary lymphoid structures compared to the control. Immunohistochemistry confirmed well-organized lymphoid structures with intact B- and T-cell populations. FXll KO mice are protected in LPS-induced septic shock and EAE models. Regarding the EAE model, FXIIa inhibition significantly reduced disease severity compared to control. In the LPS model, FXll KO mice recover within 24 hours after LPS-challenge measured subjectively and objectively by core body temperature measurement. DISCUSSION/SIGNIFICANCE OF IMPACT: The current study and previous findings suggest a novel immune signaling mechanism by which a peptide fragment of high molecular-weight kininogen (HK-D5) acts as an accelerant of both innate and adaptive immune cell chemotaxis in multiple immune contexts. This has broad implications regarding a mechanism of immune-mediated inflammation in a variety of disease states, which might be amenable to the targeting this pathway for therapeutic intent.

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P413 OXIDIZED-HEMOGLOBIN INDUCES INNATE IMMUNE CELL CHEMOTAXIS, MONOCYTE ARREST AND THEIR SUBINTIMAL MIGRATION INTO EARLY ATHEROSCLEROTIC TISSUE

Atherosclerosis Supplements ◽

10.1016/s1567-5688(10)70480-3 ◽

2010 ◽

Vol 11 (2) ◽

pp. 104

Author(s):

B. Buttari ◽

E. Profumo ◽

G. Domenici ◽

M. Leopizzi ◽

C. Di Cristofano ◽

...

Keyword(s):

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Cell Chemotaxis

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Integrative Analysis of Gene Expression Based on Multi-Omics Databases Identified CXC Chemokines as Immune Prognostic Biomarkers of Rectal Adenocarcinoma

10.21203/rs.3.rs-447142/v1 ◽

2021 ◽

Author(s):

Xiaoshuai Wang ◽

Zhiyang Hu ◽

Zefeng Du ◽

Dongchun Hong ◽

Haoyang Huang ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Rectal Adenocarcinoma ◽

Clinicopathological Features ◽

Prognostic Biomarkers ◽

Regulatory Mechanisms ◽

High Recurrence Rate ◽

Poor Survival ◽

Lower Expression ◽

Cell Chemotaxis

Abstract Background: Rectal adenocarcinoma (READ) is one of the most frequent malignancies with a high recurrence rate. CXC chemokines, as indispensable components of the immune system, are considered broadly involving in tumorigenesis by orchestrating the immune cell chemotaxis and thus affect the prognosis of READ patients. However, the values of CXC chemokines as prognostic biomarkers and potential regulatory mechanisms for READ remain unclear.Results: The expression levels of CXCL3, CXCL12, and CXCL13 were aberrant in both TCGA and ONCOMINE databases. Lower expression of CXCL3 and CXCL13 predicted poor survival of READ patients. Additionally, both CXCL3 and CXCL13 were associated with several clinicopathological features. CXCL3 and CXCL13 expressions were significantly correlated with the tumor infiltration levels of immune cells in READ tissue. CeRNA networks of mRNA-miRNA-lncRNA were constructed to reveal the potential mechanisms that regulated the expressions of CXCL3 and CXCL13. Furthermore, GSEA revealed the association between immune-related pathways and CXCL3 as well as CXCL13.Conclusions: CXCL3 and CXCL13 could be valuable prognostic biomarkers in READ. CXCL3/miR-425-5p/chr22-38_28785274–29006793.1 was identified as the most potential ceRNA network in READ. Our results might provide novel insights in READ immunotherapy.

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Two macrophage migration inhibitory factors regulate starfish larval immune cell chemotaxis

Immunology and Cell Biology ◽

10.1038/icb.2016.6 ◽

2016 ◽

Vol 94 (4) ◽

pp. 315-321 ◽

Cited By ~ 6

Author(s):

Ryohei Furukawa ◽

Kana Tamaki ◽

Hiroyuki Kaneko

Keyword(s):

Immune Cell ◽

Macrophage Migration ◽

Inhibitory Factors ◽

Cell Chemotaxis

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Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases

Scientific Reports ◽

10.1038/s41598-021-01063-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eleonora Olivotto ◽

Manuela Minguzzi ◽

Stefania D’Adamo ◽

Annalisa Astolfi ◽

Spartaco Santi ◽

...

Keyword(s):

Cellular Differentiation ◽

Gene Expression Analysis ◽

Immune Cell ◽

Protein Levels ◽

Individual Contributions ◽

Monocyte Chemotaxis ◽

Microscopy Analysis ◽

Oa Chondrocytes ◽

Confocal Microscopy Analysis ◽

Cell Chemotaxis

AbstractIKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target.

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