The Th17 Pathway in Vascular Inflammation: Culprit or Consort?

Robert, Marie; Miossec, Pierre; Hot, A.

doi:10.3389/fimmu.2022.888763

Cited by 20 publications

(13 citation statements)

References 197 publications

(261 reference statements)

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“…87,93,94 Exacerbated Th17 activation may induce and contribute to the onset or progression of autoimmune disorders such as T1D 95 and vascular inflammation. 96 The balance between Treg/ Th17 cells is critical and is responsible for generation of pro-inflammatory cytokines such as IL-17 production, which are known to facilitate the development of diabetic retinopathy. [97][98][99][100] Thus, collectively our study supports that retinopathy in human subjects with T1D is associated with a dysregulated systemic RAS and profound gut permeability defects which triggered activation of components of both the adaptive (B-cells, Treg/Th17, DCs) and innate (granulopoiesis) immune response and changes in gut derived ILC1s.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Prasad

Floyd

Dupont

et al. 2023

Circulation Research

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BACKGROUND: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes. METHODS: Type 1 diabetes individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and PGN [peptidoglycan]), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells ( Vil-Cre.hAce2KI-Akita ) were similarly examined. After 9 months of type 1 diabetes, circulatory, enteral, and ocular end points were assessed. RESULTS: Type 1 diabetes subjects exhibit elevations in gut-derived circulating immune cells (Th17 and ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3β/c-Myc-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. CONCLUSIONS: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.

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Section: Discussionmentioning

confidence: 99%

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Prasad

Floyd

Dupont

et al. 2023

Circulation Research

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“…Despite a pivotal role, the Th2 response alone cannot fully explain other EGPA manifestations, such as granulomas and vascular inflammation. An increased frequency in IL-17-producing CD4 þ T cells (Th17) has been described in EGPA compared to healthy or asthmatic controls and during active disease compared to inactive EGPA [14]. Moreover, a defective activity of regulatory T cells (Treg), which exert a suppressive effect on Th17 cells, has been described during active EGPA.…”

Section: Other Cells In Eosinophilic Granulomatosis With Polyangiitis...mentioning

confidence: 99%

Biologics for eosinophilic granulomatosis with polyangiitis

Caminati

Maule

Bello

et al. 2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewThe link between severe asthma and eosinophilic granulomatosis with polyangiitis (EGPA) in terms of pathophysiological background, clinical manifestations and disease evolution has leaded to investigate the relevance of anti T2 monoclonal antibodies licensed for severe asthma patients as a treatment option for EGPA. The present review aimed to provide un update on EGPA pathophysiology and to critically summarize the most robust evidence coming from trials and real-life setting on the use of anti T2 biologics in EGPA patients.Recent findingsMepolizumab, an anti-interleukin-5 monoclonal antibody, is the only biologic drug targeting eosinophilic inflammation currently approved for EGPA treatment at the dose of 300 mg/4 weeks. Its use is restricted by the American College of Rheumatology guidelines to specific diseases phases and severity grades. However the most appropriate mepolizumab positioning and dose is still under investigation in the real life practice, which is providing an increasing amount of evidence confirming its efficacy, alone or in combination with other options in different disease stages. The relevance of other monoclonal antibodies interfering with T2 inflammation, including omalizumab and benralizumab, is under investigation but the evidence is still scarceSummaryTaking into account the suboptimal medium-long term safety profile of conventional EGPA treatments, the opportunity of selectively targeting eosinophilic inflammation certainly represents a revolutionary approach. However, further real-word evidence is required to effectively position the new treatments in the light of the disease complexity, including different immunological drivers, and individual variability.

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“…This is a critical element of immune regulation since excessive IL‐6 production increases Th17 cells important in mediation of allograft rejection. We now know that Th17 cells contribute to allograft injury, suppress Treg cell development and stimulate profibrotic cytokines resulting in progressive declines in renal function and graft loss 18 …”

Section: Il‐6: a Cytokine Important In Immune Cell Activationmentioning

confidence: 99%

“…We now know that Th17 cells contribute to allograft injury, suppress Treg cell development and stimulate profibrotic cytokines resulting in progressive declines in renal function and graft loss. 18…”

Section: Il-6: a C Y Tok Ine Imp Ortant In Immune Cell Ac Tivati Onmentioning

confidence: 99%

Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts

Jordan

Ammerman

Huang

et al. 2022

American Journal of Transplantation

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However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome.Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cellmediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.

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The Th17 Pathway in Vascular Inflammation: Culprit or Consort?

Cited by 20 publications

References 197 publications

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes

Biologics for eosinophilic granulomatosis with polyangiitis

Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts

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