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Article ; Online: Animal Models for Toxoplasma gondii Infection.

S Subauste, Carlos / Hubal, Alyssa

Current protocols

2023 Volume 3, Issue 9, Page(s) e871

Abstract: Toxoplasma gondii is an obligate intracellular protozoan parasite that commonly infects mammals and birds throughout the world. This protocol describes murine models of acute T. gondii infection, toxoplasmic encephalitis and toxoplasma retinochoroiditis. ...

Abstract	Toxoplasma gondii is an obligate intracellular protozoan parasite that commonly infects mammals and birds throughout the world. This protocol describes murine models of acute T. gondii infection, toxoplasmic encephalitis and toxoplasma retinochoroiditis. T. gondii infection in severe combined immunodeficient (SCID) mice, deficient in T and B cells, has allowed for the study of T cell-independent mechanisms of defense against intracellular organisms, as described here. The uracil auxotroph strain cps1-1 and temperature-sensitive mutant strains of T. gondii induce protection against challenge with virulent strains of the parasite. They have allowed studies of immunization and adoptive-transfer experiments. A protocol is provided for infection with these mutant strains. The EGS strain of T. gondii has the unique feature of spontaneously forming tissue cysts in cell culture. Dual fluorescent reporter stains of this strain have allowed the study of tachyzoite to bradyzoite transitions in vitro and in vivo. A protocol for in vitro and in vivo growth of this strain and tissue cyst isolation is provided. Genetic manipulation of T. gondii and mice has led to the development of parasites that express fluorescent proteins as well as mice with fluorescently labeled leukocytes. This together with the use of T. gondii that express model antigens and transgenic mice that express the appropriate T cell receptor have facilitated the in vivo study of parasite host-interaction. In addition, parasites that express bioluminescent markers have made it possible to study the dynamics of infection in real time using bioluminescence imaging. Support protocols present methodology for evaluation of progression of infection and immune response to the parasite that includes these newer methodologies. In addition, support protocols address the maintenance of T. gondii tissue cysts and tachyzoites, as well as preparation of T. gondii lysate antigens. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Induction of acute T. gondii infection in mice Basic Protocol 2: Model of toxoplasmic encephalitis and toxoplasma retinochoroiditis in chronically infected mice Basic Protocol 3: Assessment of T. gondii invasion into neural tissue Basic Protocol 4: T. gondii infection in scid/scid (SCID) mice Basic Protocol 5: Infection with the uracil auxotroph strain CPS1-1 or the temperature-sensitive TS-4 strain of T. gondii Basic Protocol 6: In vivo and in vitro maintenance of the EGS strain of T. gondii Support Protocol 1: Assessment of progression of infection and immune response to T. gondii Support Protocol 2: Maintenance of a bank of T. gondii cysts of the ME49 strain Support Protocol 3: Maintenance of T. gondii tachyzoites using human foreskin fibroblasts Support Protocol 4: Maintenance of T. gondii tachyzoites in mice Support Protocol 5: Preparation of T. gondii lysate antigens Support Protocol 6: Isolation of T. gondii tissue cysts from brain.
MeSH term(s)	Humans ; Animals ; Mice ; Mice, SCID ; Toxoplasmosis, Ocular ; Toxoplasmosis, Cerebral ; Models, Animal ; Antigens, Viral, Tumor ; Coloring Agents ; Cysts ; Encephalitis ; Mammals
Chemical Substances	Antigens, Viral, Tumor ; Coloring Agents
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.871
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Article ; Online: Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy.

Portillo, Jose-Andres C / Pfaff, Amelia / Vos, Sarah / Weng, Matthew / Nagaraj, Ram H / Subauste, Carlos S

Cells

2024 Volume 13, Issue 5

Abstract: CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven ... ...

Abstract	CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven inflammatory disorders. What drives CD40 upregulation in the diabetic retina remains unknown. We examined the role of advanced glycation end products (AGEs) in CD40 upregulation in endothelial cells and Müller cells. Human endothelial cells and Müller cells were incubated with unmodified or methylglyoxal (MGO)-modified fibronectin. CD40 expression was assessed by flow cytometry. The expression of ICAM-1 and CCL2 was examined by flow cytometry or ELISA after stimulation with CD154 (CD40 ligand). The expression of carboxymethyl lysine (CML), fibronectin, and laminin as well as CD40 in endothelial and Müller cells from patients with DR was examined by confocal microscopy. Fibronectin modified by MGO upregulated CD40 in endothelial and Müller cells. CD40 upregulation was functionally relevant. MGO-modified fibronectin enhanced CD154-driven upregulation of ICAM-1 and CCL2 in endothelial and Müller cells. Increased CD40 expression in endothelial and Müller cells from patients with DR was associated with increased CML expression in fibronectin and laminin. These findings identify AGEs as inducers of CD40 upregulation in endothelial and Müller cells and enhancers of CD40-dependent pro-inflammatory responses. CD40 upregulation in these cells is associated with higher CML expression in fibronectin and laminin in patients with DR. This study revealed that CD40 and AGEs, two important drivers of DR, are interconnected.
MeSH term(s)	Humans ; Diabetic Retinopathy/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Fibronectins/metabolism ; Ependymoglial Cells/metabolism ; Endothelial Cells/metabolism ; Magnesium Oxide/metabolism ; Retina/metabolism ; CD40 Antigens/metabolism ; CD40 Ligand/metabolism ; Laminin/metabolism ; Glycation End Products, Advanced/metabolism ; Diabetes Mellitus/metabolism
Chemical Substances	Intercellular Adhesion Molecule-1 (126547-89-5) ; Fibronectins ; Magnesium Oxide (3A3U0GI71G) ; CD40 Antigens ; CD40 Ligand (147205-72-9) ; Laminin ; Glycation End Products, Advanced
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13050429
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Article ; Online: Metastatic Merkel Cell Carcinoma Within a Cortisol-producing Adrenal Adenoma.

Cutrone, Lauren / Subauste, Jose / Gomez-Sanchez, Celso / Joiner, Sarah

JCEM case reports

2023 Volume 1, Issue 5, Page(s) luad100

Abstract: A 54-year-old man with hypertension, type 2 diabetes mellitus, and a history of Merkel cell carcinoma (MCC) of the right thigh presented to the emergency department with a 4-day history of right lower-quadrant abdominal pain associated with constipation ... ...

Abstract	A 54-year-old man with hypertension, type 2 diabetes mellitus, and a history of Merkel cell carcinoma (MCC) of the right thigh presented to the emergency department with a 4-day history of right lower-quadrant abdominal pain associated with constipation and decreased appetite. Workup showed a heterogenous 6-cm right adrenal mass with macroscopic fat. Imaging was suggestive of benign pathology. Hormonal workup for the adrenal nodule led to the diagnosis of Cushing syndrome. The patient underwent a right adrenalectomy for Cushing syndrome with pathology revealing a 6.5-cm adrenocortical adenoma harboring a 2-cm, well-circumscribed neuroendocrine tumor consistent with metastatic MCC. Adrenal collision tumors are exceedingly rare. This case describes a collision tumor that has not previously been identified-a cortisol-producing adrenal adenoma and metastatic MCC.
Language	English
Publishing date	2023-09-20
Publishing country	England
Document type	Case Reports
ISSN	2755-1520
ISSN (online)	2755-1520
DOI	10.1210/jcemcr/luad100
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Article ; Online: A cell-penetrating CD40-TRAF2,3 blocking peptide diminishes inflammation and neuronal loss after ischemia/reperfusion.

Portillo, Jose-Andres C / Yu, Jin-Sang / Hansen, Samuel / Kern, Timothy S / Subauste, M Cecilia / Subauste, Carlos S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Volume 35, Issue 3, Page(s) e21412

Abstract: While the administration of anti-CD154 mAbs in mice validated the CD40-CD154 pathway as a target against inflammatory disorders, this approach caused thromboembolism in humans (unrelated to CD40 inhibition) and is expected to predispose to opportunistic ... ...

Abstract	While the administration of anti-CD154 mAbs in mice validated the CD40-CD154 pathway as a target against inflammatory disorders, this approach caused thromboembolism in humans (unrelated to CD40 inhibition) and is expected to predispose to opportunistic infections. There is a need for alternative approaches to inhibit CD40 that avoid these complications. CD40 signals through TRAF2,3 and TRAF6-binding sites. Given that CD40-TRAF6 is the pathway that stimulates responses key for cell-mediated immunity against opportunistic pathogens, we examined the effects of pharmacologic inhibition of CD40-TRAF2,3 signaling. We used a model of ischemia/reperfusion (I/R)-induced retinopathy, a CD40-driven inflammatory disorder. Intravitreal administration of a cell-penetrating CD40-TRAF2,3 blocking peptide impaired ICAM-1 upregulation in retinal endothelial cells and CXCL1 upregulation in endothelial and Müller cells. The peptide reduced leukocyte infiltration, upregulation of NOS2/COX-2/TNF-α/IL-1β, and ameliorated neuronal loss, effects that mimic those observed after I/R in Cd40-/- mice. While a cell-penetrating CD40-TRAF6 blocking peptide also diminished I/R-induced inflammation, this peptide (but not the CD40-TRAF2,3 blocking peptide) impaired control of the opportunistic pathogen Toxoplasma gondii in the retina. Thus, inhibition of the CD40-TRAF2,3 pathway is a novel and potent approach to reduce CD40-induced inflammation, while likely diminishing the risk of opportunistic infections that would otherwise accompany CD40 inhibition.
MeSH term(s)	Animals ; CD40 Antigens/drug effects ; CD40 Antigens/genetics ; CD40 Antigens/metabolism ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Female ; Humans ; Inflammation/drug therapy ; Inflammation/metabolism ; Ischemia/drug therapy ; Ischemia/metabolism ; Male ; Mice ; Neurons/cytology ; Neurons/drug effects ; Peptides/pharmacology ; Reperfusion/methods ; Signal Transduction/drug effects ; Signal Transduction/physiology ; TNF Receptor-Associated Factor 2/drug effects ; TNF Receptor-Associated Factor 2/metabolism
Chemical Substances	CD40 Antigens ; Peptides ; TNF Receptor-Associated Factor 2
Language	English
Publishing date	2021-03-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201903203RR
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Article ; Online: CD40 Expressed in Endothelial Cells Promotes Upregulation of ICAM-1 But Not Pro-Inflammatory Cytokines, NOS2 and P2X7 in the Diabetic Retina.

Yu, Jin-Sang / Daw, Jad / Portillo, Jose-Andres C / Subauste, Carlos S

Investigative ophthalmology & visual science

2021 Volume 62, Issue 12, Page(s) 22

Abstract: Purpose: CD40 is an upstream inducer of inflammation in the diabetic retina. CD40 is upregulated in retinal endothelial cells in diabetes. The purpose of this study was to determine whether expression of CD40 in endothelial cells is sufficient to ... ...

Abstract	Purpose: CD40 is an upstream inducer of inflammation in the diabetic retina. CD40 is upregulated in retinal endothelial cells in diabetes. The purpose of this study was to determine whether expression of CD40 in endothelial cells is sufficient to promote inflammatory responses in the retina of diabetic mice. Methods: Transgenic mice with CD40 expression restricted to endothelial cells (Trg-CD40 EC), transgenic control mice (Trg-Ctr), B6, and CD40-/- mice were made diabetic using streptozotocin. Leukostasis was assessed using FITC-conjugated ConA. Pro-inflammatory molecule expression was examined by real-time PCR, immunohistochemistry, ELISA, or flow cytometry. Release of ATP was assessed by ATP bioluminescence. Results: Diabetic B6 and Trg-CD40 EC mice exhibited increased retinal mRNA levels of ICAM-1, higher ICAM-1 expression in endothelial cells, and increased leukostasis. These responses were not detected in diabetic mice that lacked CD40 (CD40-/- and Trg-Ctr). Diabetic B6 but not Trg-CD40 EC mice upregulated TNF-α, IL-1β, and NOS2 mRNA levels. CD40 stimulation in retinal endothelial cells upregulated ICAM-1 but not TNF-α, IL-1β, or NOS2. CD40 ligation did not trigger ATP release by retinal endothelial cells or pro-inflammatory cytokine production in bystander myeloid cells. In contrast to diabetic B6 mice, diabetic Trg-CD40 EC mice did not upregulate P2X7 mRNA levels in the retina. Conclusions: Endothelial cell CD40 promotes ICAM-1 upregulation and leukostasis. In contrast, endothelial cell CD40 does not lead to pro-inflammatory cytokine and NOS2 upregulation likely because it does not activate purinergic-mediated pro-inflammatory molecule expression by myeloid cells or induce expression of these pro-inflammatory molecules in endothelial cells.
MeSH term(s)	Animals ; CD40 Antigens/genetics ; Cytokines/genetics ; Diabetes Mellitus, Experimental/genetics ; Diabetic Retinopathy/genetics ; Endothelial Cells/metabolism ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression Regulation/physiology ; Humans ; Intercellular Adhesion Molecule-1/genetics ; Leukostasis ; Luminescent Measurements ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nitric Oxide Synthase Type II/genetics ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Receptors, Purinergic P2X7/genetics ; Retinal Vessels/cytology ; Up-Regulation
Chemical Substances	CD40 Antigens ; Cytokines ; Icam1 protein, mouse ; P2rx7 protein, mouse ; RNA, Messenger ; Receptors, Purinergic P2X7 ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39)
Language	English
Publishing date	2021-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.62.12.22
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Article ; Online: Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii.

Corcino, Yalitza Lopez / Portillo, Jose-Andres C / Subauste, Carlos S

Scientific reports

2019 Volume 9, Issue 1, Page(s) 669

Abstract: Little is known about strategies used by pathogens to facilitate CNS invasion. Toxoplasma gondii reaches the CNS by circulating in blood within leukocytes or as extracellular tachyzoites. T. gondii induces EGFR signaling in vitro during invasion of ... ...

Abstract	Little is known about strategies used by pathogens to facilitate CNS invasion. Toxoplasma gondii reaches the CNS by circulating in blood within leukocytes or as extracellular tachyzoites. T. gondii induces EGFR signaling in vitro during invasion of mammalian cells. We examined the effects of endothelial cell EGFR on CNS invasion. Transgenic mice whose endothelial cells expressed a dominant negative (DN) EGFR (inhibits EGFR signaling) exhibited diminished parasite load and histopathology in the brain and retina after T. gondii infection. I.V. administration of infected leukocytes or extracellular tachyzoites led to reduced parasite loads in mice with DN EGFR. This was not explained by enhanced immunity or reduced leukocyte recruitment. Endothelial cell infection is key for CNS invasion. Parasite foci in brain endothelial cells were reduced by DN EGFR. DN EGFR in these cells led to recruitment of the autophagy protein LC3 around T. gondii and spontaneous parasite killing dependent on the autophagy protein ULK1 and lysosomal enzymes. The autophagy inhibitor 3-MA prevented DN EGFR mice from exhibiting reduced CNS invasion. Altogether, EGFR is a novel regulator of T. gondii invasion of neural tissue, enhancing invasion likely by promoting survival of the parasite within endothelial cells.
MeSH term(s)	Animals ; Autophagy ; Brain/parasitology ; Brain/pathology ; Endothelial Cells/metabolism ; Endothelial Cells/parasitology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Female ; Host-Parasite Interactions/physiology ; Immunity, Humoral ; Leukocytes/pathology ; Mice, Transgenic ; Parasite Load ; Retina/parasitology ; Retina/pathology ; Toxoplasma/pathogenicity ; Toxoplasmosis/immunology ; Toxoplasmosis/metabolism ; Toxoplasmosis/parasitology
Chemical Substances	EGFR protein, mouse (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2019-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-36724-2
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Article: Fatty Liver Disease, Women, and Aldosterone: Finding a Link in the Jackson Heart Study.

Kumar, Aditi / Blackshear, Chad / Subauste, Jose S / Esfandiari, Nazanene H / Oral, Elif Arioglu / Subauste, Angela R

Journal of the Endocrine Society

2017 Volume 1, Issue 5, Page(s) 460–469

Abstract: Context: Fatty liver disease is one of the most common forms of chronic liver disease. The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of fatty liver.: Objective: Determine the relationship between fatty liver and ... ...

Abstract	Context: Fatty liver disease is one of the most common forms of chronic liver disease. The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of fatty liver. Objective: Determine the relationship between fatty liver and aldosterone in a large cohort study. Design: Community-based, observational cohort study of African Americans. Setting: The original Jackson Heart Study cohort enrolled African American participants from the Jackson, Mississippi, metropolitan area in Hinds, Madison, and Rankin Counties. Participants: Our study population consisted of 2507 Jackson Heart Study participants (1625 women and 882 men) who had liver attenuation measured per computed tomography scans, had aldosterone measurements, and were not taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or mineralocorticoid receptor antagonists. Intervention: There was no intervention. Main outcome measure: Liver attenuation on computed tomography scans. Results: Univariate regression analysis demonstrated a statistically significant correlation between aldosterone levels and liver attenuation. Each doubling of aldosterone was associated with 1.08 Hounsfield unit decrease (95% confidence interval, 1.47 to -0.69, Conclusion: Our data demonstrate a positive association between aldosterone levels and fatty liver in African American women.
Language	English
Publishing date	2017-03-22
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN	2472-1972
DOI	10.1210/js.2017-00055
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Article: Primary immunodeficiencies and susceptibility to parasitic infections.

Subauste, C S

Parasite immunology

2006 Volume 28, Issue 11, Page(s) 567–575

Abstract: Primary immunodeficiencies are important disorders because they typically cause severe illness in affected patients. In addition, these diseases provide a unique glimpse at the underpinnings of the immune system in humans. Susceptibility to infections, ... ...

Abstract	Primary immunodeficiencies are important disorders because they typically cause severe illness in affected patients. In addition, these diseases provide a unique glimpse at the underpinnings of the immune system in humans. Susceptibility to infections, including those caused by parasites, is a hallmark of these immune defects. Understanding the association between primary immunodeficiencies and parasitic infections will likely improve our grasp on the mechanisms of defense against these pathogens.
MeSH term(s)	Disease Susceptibility/immunology ; Genetic Predisposition to Disease ; Humans ; Immunocompromised Host/immunology ; Immunologic Deficiency Syndromes/classification ; Immunologic Deficiency Syndromes/diagnosis ; Immunologic Deficiency Syndromes/immunology ; Parasitic Diseases/epidemiology ; Parasitic Diseases/immunology ; Parasitic Diseases/parasitology
Language	English
Publishing date	2006-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	424444-8
ISSN	1365-3024 ; 0141-9838
ISSN (online)	1365-3024
ISSN	0141-9838
DOI	10.1111/j.1365-3024.2006.00890.x
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Article ; Online: Disruption of retinal inflammation and the development of diabetic retinopathy in mice by a CD40-derived peptide or mutation of CD40 in Müller cells.

Portillo, Jose-Andres C / Yu, Jin-Sang / Vos, Sarah / Bapputty, Reena / Lopez Corcino, Yalitza / Hubal, Alyssa / Daw, Jad / Arora, Sahil / Sun, Wenyu / Lu, Zheng-Rong / Subauste, Carlos S

Diabetologia

2022 Volume 65, Issue 12, Page(s) 2157–2171

Abstract: Aims/hypothesis: CD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by purinergic receptor (P2X: Methods: B6 and transgenic mice with Müller ...

Abstract	Aims/hypothesis: CD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by purinergic receptor (P2X Methods: B6 and transgenic mice with Müller cell-restricted expression of wild-type (WT) CD40 or CD40 with mutations in TNF receptor-associated factor (TRAF) binding sites were made diabetic using streptozotocin. Leucostasis was assessed using FITC-conjugated concanavalin A. Histopathology was examined in the retinal vasculature. Expression of inflammatory molecules and phospho-Tyr783 PLCγ1 (p-PLCγ1) were assessed using real-time PCR, immunoblot and/or immunohistochemistry. Release of ATP and cytokines were measured by ATP bioluminescence and ELISA, respectively. Results: Human Müller cells with CD40 ΔT2,3 (lacks TRAF2,3 binding sites) were unable to phosphorylate PLCγ1 and release ATP in response to CD40 ligation, and could not induce TNF-α/IL-1β secretion in bystander myeloid cells. CD40-TRAF signalling acted via Src to induce PLCγ1 phosphorylation. Diabetic mice in which WT CD40 in Müller cells was replaced by CD40 ΔT2,3 failed to exhibit phosphorylation of PLCγ1 in these cells and upregulate P2X Conclusions/interpretation: CD40-TRAF2,3 signalling activated the CD40-PLCγ1-ATP-P2X
MeSH term(s)	Mice ; Humans ; Animals ; Ependymoglial Cells/metabolism ; Diabetic Retinopathy/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; TNF Receptor-Associated Factor 2/genetics ; CD40 Antigens ; Retina/metabolism ; Inflammation/metabolism ; Cytokines/metabolism ; Peptides ; Adenosine Triphosphate/metabolism ; Mutation
Chemical Substances	Tumor Necrosis Factor-alpha ; TNF Receptor-Associated Factor 2 ; CD40 Antigens ; Cytokines ; Peptides ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-08-03
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-022-05775-6
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Article ; Online: Blockade of CD40-TRAF2,3 or CD40-TRAF6 is sufficient to inhibit pro-inflammatory responses in non-haematopoietic cells.

Portillo, Jose-Andres C / Greene, Jennifer A / Schwartz, Isaac / Subauste, Maria Cecilia / Subauste, Carlos S

Immunology

2014 Volume 144, Issue 1, Page(s) 21–33

Abstract: Inhibition of the CD40-CD154 pathway controls inflammatory disorders. Unfortunately, administration of anti-CD154 monoclonal antibodies causes thromboembolism. Blockade of signalling downstream of CD40 may represent an approach to treat CD40-driven ... ...

Abstract	Inhibition of the CD40-CD154 pathway controls inflammatory disorders. Unfortunately, administration of anti-CD154 monoclonal antibodies causes thromboembolism. Blockade of signalling downstream of CD40 may represent an approach to treat CD40-driven inflammatory disorders. Blocking tumour necrosis factor receptor-associated factor 6 (TRAF6) signalling downstream of CD40 in MHC II(+) cells diminishes inflammation. However, CD40-TRAF6 blockade may cause immunosuppression. We examined the role of CD40-TRAF2,3 and CD40-TRAF6 signalling in the development of pro-inflammatory responses in human non-haematopoietic and monocytic cells. Human aortic endothelial cells, aortic smooth muscle cells, renal proximal tubule epithelial cells, renal mesangial cells and monocytic cells were transduced with retroviral vectors that encode wild-type CD40, CD40 with a mutation that prevents TRAF2,3 recruitment (ΔT2,3), TRAF6 recruitment (ΔT6) or both TRAF2,3 plus TRAF6 recruitment (ΔT2,3,6). Non-haematopoietic cells that expressed CD40 ΔT2,3 exhibited marked inhibition in CD154-induced up-regulation of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 (ICAM-1), monocyte chemotactic protein 1 (MCP-1), tissue factor and matrix metalloproteinase 9. Similar results were obtained with cells that expressed CD40 ΔT6. Although both mutations impaired ICAM-1 up-regulation in monocytic cells, only expression of CD40 ΔT6 reduced MCP-1 and tissue factor up-regulation in these cells. Treatment of endothelial and smooth muscle cells with cell-permeable peptides that block CD40-TRAF2,3 or CD40-TRAF6 signalling impaired pro-inflammatory responses. In contrast, while the CD40-TRAF2,3 blocking peptide did not reduce CD154-induced dendritic cell maturation, the CD40-TRAF6 blocking peptide impaired this response. Hence, preventing CD40-TRAF2,3 or CD40-TRAF6 interaction inhibits pro-inflammatory responses in human non-haematopoietic cells. In contrast to inhibition of CD40-TRAF6 signalling, inhibition of CD40-TRAF2,3 signalling did not impair dendritic cell maturation. Blocking CD40-TRAF2,3 signalling may control CD40-CD154-dependent inflammatory disorders.
MeSH term(s)	Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; CD40 Antigens/antagonists & inhibitors ; CD40 Antigens/genetics ; CD40 Antigens/immunology ; CD40 Ligand/genetics ; CD40 Ligand/immunology ; Cell Line ; Chemokine CCL2/genetics ; Chemokine CCL2/immunology ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Endothelial Cells/immunology ; Endothelial Cells/pathology ; Humans ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/immunology ; Intercellular Adhesion Molecule-1/genetics ; Intercellular Adhesion Molecule-1/immunology ; Mesangial Cells/immunology ; Mesangial Cells/pathology ; Mice ; Myocytes, Smooth Muscle/immunology ; Myocytes, Smooth Muscle/pathology ; Peptides/pharmacology ; Peroxidases/genetics ; Peroxidases/immunology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Signal Transduction/immunology ; TNF Receptor-Associated Factor 2/antagonists & inhibitors ; TNF Receptor-Associated Factor 2/genetics ; TNF Receptor-Associated Factor 2/immunology ; TNF Receptor-Associated Factor 3/antagonists & inhibitors ; TNF Receptor-Associated Factor 3/genetics ; TNF Receptor-Associated Factor 3/immunology ; TNF Receptor-Associated Factor 6/antagonists & inhibitors ; TNF Receptor-Associated Factor 6/genetics ; TNF Receptor-Associated Factor 6/immunology ; Thromboplastin/genetics ; Thromboplastin/immunology ; Up-Regulation/drug effects ; Up-Regulation/genetics ; Up-Regulation/immunology
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; CCL2 protein, human ; CD40 Antigens ; Chemokine CCL2 ; ICAM1 protein, human ; Peptides ; TNF Receptor-Associated Factor 2 ; TNF Receptor-Associated Factor 3 ; TNF Receptor-Associated Factor 6 ; TRAF3 protein, human ; Intercellular Adhesion Molecule-1 (126547-89-5) ; CD40 Ligand (147205-72-9) ; Thromboplastin (9035-58-9) ; Peroxidases (EC 1.11.1.-) ; microperoxidase (EC 1.11.1.-)
Language	English
Publishing date	2014-07-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.12361
Database	MEDical Literature Analysis and Retrieval System OnLINE

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