scholarly journals Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function

2016 ◽  
Vol 113 (41) ◽  
pp. E6162-E6171 ◽  
Author(s):  
Sirish K. Ippagunta ◽  
Ruchika Gangwar ◽  
David Finkelstein ◽  
Peter Vogel ◽  
Stephane Pelletier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Process ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Innate Immune ◽  
Negative Regulator ◽  
Specific Gene ◽  
Innate Immune Cells ◽  
Chemokine Production

Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17–induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Blood ◽  
2011 ◽  
Vol 117 (16) ◽  
pp. 4273-4283 ◽  
Author(s):  
Thomas Weichhart ◽  
Michael Haidinger ◽  
Karl Katholnig ◽  
Chantal Kopecky ◽  
Marko Poglitsch ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Clinical Importance ◽  
Innate Immune ◽  
Negative Regulator ◽  
Innate Immune Cells ◽  
Myeloid Dendritic Cells ◽  
Mtor Inhibition ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory

Abstract A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-κB and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. Renal transplant patients receiving rapamycin but not those receiving calcineurin inhibitors displayed a state of innate immune cell hyper-responsiveness despite the concurrent use of GC. Finally, mTOR inhibition was able to override the healing phenotype of dexamethasone in a murine lipopolysaccharide shock model. Collectively, these data identify a novel link between the glucocorticoid receptor and mTOR in innate immune cells, which is of considerable clinical importance in a variety of disorders, including allogeneic transplantation, autoimmune diseases, and cancer.

scholarly journals Contribution ofIn Vivoand Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Isabelle Lorthois ◽  
Daniel Asselineau ◽  
Nathalie Seyler ◽  
Roxane Pouliot
Keyword(s):  
Immune Cells ◽  
Skin Disease ◽  
Immune Cell ◽  
3D Models ◽  
Current Data ◽  
Innate Immune ◽  
Innate Immune Cells

Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensionalin vitromodels have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use ofin vivoand 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease.

scholarly journals Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3

2019 ◽  
Vol 216 (7) ◽  
pp. 1700-1723 ◽  
Author(s):  
Matthias von Gamm ◽  
Annalisa Schaub ◽  
Alisha N. Jones ◽  
Christine Wolf ◽  
Gesine Behrens ◽  
...  
Keyword(s):  
Immune Cells ◽  
Germinal Center ◽  
Immune Cell ◽  
Innate Immune ◽  
Immune Homeostasis ◽  
Innate Immune Cells ◽  
Interferon Pathway ◽  
Deficient Mice ◽  
Germinal Center Formation

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed Regnase-3–deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell–specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade, and regulate mRNAs, such as Zc3h12a (Regnase-1), in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.

scholarly journals Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

2021 ◽  
Author(s):  
Ivana Y Quiroga ◽  
Aimee E Cruikshank ◽  
Kathleen S M Reed ◽  
Marielle L Bond ◽  
Baggio A Evangelista ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Immune Cells ◽  
Immune Cell ◽  
Neuronal Damage ◽  
Transcriptional Response ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cellular Models ◽  
A Genome

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e. microglia), which culminates in neuronal damage and cognitive decline. In order to test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. To address this, we used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ. We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes similar to those observed in disease associated microglia present in the AD brain, suggesting the potential suitability of this model to study AD-related neuroinflammation.

scholarly journals Oral Exposure to House Dust Mite Activates Intestinal Innate Immunity

Foods ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 561
Author(s):  
Sara Benedé ◽  
Leticia Pérez-Rodríguez ◽  
Mónica Martínez-Blanco ◽  
Elena Molina ◽  
Rosina López-Fandiño
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Immune Cells ◽  
Oral Route ◽  
Innate Immune ◽  
Oral Exposure ◽  
Lymphoid Tissues ◽  
Innate Immune Cells ◽  
Dust Mite

Scope: House dust mite (HDM) induces Th2 responses in lungs and skin, but its effects in the intestine are poorly known. We aimed to study the involvement of HDM in the initial events that would promote sensitization through the oral route and eventually lead to allergy development. Methods and results: BALB/c mice were exposed intragastrically to proteolytically active and inactive HDM, as such, or in combination with egg white (EW), and inflammatory and type 2 responses were evaluated. Oral administration of HDM, by virtue of its proteolytic activity, promoted the expression, in the small intestine, of genes encoding tight junction proteins, proinflammatory and Th2-biasing cytokines, and it caused expansion of group 2 innate immune cells, upregulation of Th2 cytokines, and dendritic cell migration and activation. In lymphoid tissues, its proteolytically inactivated counterpart also exerted an influence on the expression of surface DC molecules involved in interactions with T cells and in Th2 cell differentiation, which was confirmed in in vitro experiments. However, in our experimental setting we did not find evidence for the promotion of sensitization to coadministered EW. Conclusion: Orally administered HDM upregulates tissue damage factors and also acts as an activator of innate immune cells behaving similarly to potent oral Th2 adjuvants.

Abstract 1772: Cardiomyocyte Damage-Released S100A1 Protein Evokes A Proinflammatory Phenotype In Cardiac Fibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
David Rohde ◽  
Melanie Boerries ◽  
Herzog Nicole ◽  
Gang Qiu ◽  
Philipp Ehlermann ◽  
...  
Keyword(s):  
Western Blotting ◽  
Immune Cells ◽  
Nuclear Translocation ◽  
Cardiac Fibroblasts ◽  
Innate Immune ◽  
Host Cells ◽  
Boyden Chamber ◽  
Innate Immune Cells ◽  
Danger Signal

Background: S100A1, a cardiomyocyte specific inotropic calcium sensor protein, is released from infarcted human myocardium in the extracellular environment and circulation, reaching peak serum levels (1–2 μM) 8–9 hours after clinical onset. As growing evidence indicates that S100 proteins can act as pre-existing danger signals triggering the innate immune system into action upon release from injured host cells, we hypothesized that damage-released S100A1 can act as a cardiac danger signal alerting innate immune cells. Methods and Results: Here we report for the first time that necrotic cardiomyocytes release S100A1 protein in vitro, which is exclusively internalized by cardiac fibroblasts (CFs) in a clathrin- and caveolin-independent manner as shown by IF. Internalized S100A1 specifically activated MAPKs/SAPKs (p38, ERK1/2 and JNK) resulting in nuclear translocation of p65 (NF-kB) as assessed by Western blotting, EMSA and IF. In turn, S100A1 triggered an inflammatory gene program in CFs including enhanced expression of adhesion molecules, integrins, chemokines and cytokines including I-CAM, V-CAM, CD11b/18, IL1-alpha, MCP-1, TNF-alpha, SDF-1 among others as obtained by RT-PCR, Western blotting and ELISA. This resulted in enhanced chemoattraction and adhesion of monocytotic and stem cells to S100A1-activated CF as shown by Boyden-chamber and adhesion assays. In line with their proinflammatory transition, S100A1-activated CFs exhibited decreased collagen-1/-3 expression and de-novo collagen production, enhanced collagenolytic MMP-9 abundance and activity and increased levels of the antiangiogenic matricellular factor thrombospondin-2 reflecting extracellular matrix net degradation. Importantly, the immun-modulatory and antifibrotic actions of S100A1 protein in vitro were restricted to CFs, RAGE independent and occurred at concentrations (0.1–1 μM) that were found in patients after AMI. Conclusion: Our in vitro results indicate that S100A1 has the properties of a pre-exisiting endogenous cardiomyocyte danger signal transforming cardiac fibroblasts into immunmodulatory cells that might recruit innate immune cells to the site of cardiac injury and link cardiomyocyte damage to post-MI inflammation.

scholarly journals Hyperglycemic Memory of Innate Immune Cells Promotes In Vitro Proinflammatory Responses of Human Monocytes and Murine Macrophages

2021 ◽  
pp. ji1901348
Author(s):  
Kathrin Thiem ◽  
Samuel T. Keating ◽  
Mihai G. Netea ◽  
Niels P. Riksen ◽  
Cees J. Tack ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Human Monocytes ◽  
Murine Macrophages ◽  
Proinflammatory Responses

Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus

Gut ◽  
2020 ◽  
Vol 69 (12) ◽  
pp. 2203-2213 ◽  
Author(s):  
Anton Lutckii ◽  
Benedikt Strunz ◽  
Anton Zhirkov ◽  
Olga Filipovich ◽  
Elena Rukoiatkina ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Cell Maturation ◽  
Innate Immune Cells ◽  
B Cell Maturation ◽  
Exposed Uninfected

ObjectivesVertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates.DesignTo address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age.ResultsAs expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines.ConclusionOur data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.

scholarly journals Engineering advanced logic and distributed computing in human CAR immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jang Hwan Cho ◽  
Atsushi Okuma ◽  
Katri Sofjan ◽  
Seunghee Lee ◽  
James J. Collins ◽  
...  
Keyword(s):  
Immune Cells ◽  
Communication Channel ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Complex Phenotypes ◽  
Car T ◽  
Different Cell Types ◽  
Multiple Immune Cell

AbstractThe immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.

scholarly journals Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

2015 ◽  
Vol 309 (12) ◽  
pp. H2042-H2057 ◽  
Author(s):  
Sanjukta Chakraborty ◽  
Scott D. Zawieja ◽  
Wei Wang ◽  
Yang Lee ◽  
Yuan J. Wang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Contractile Activity ◽  
Macrophage Polarization ◽  
Lymphatic Vessels ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lymphatic Function ◽  
Inflammatory Conditions ◽  
Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

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