Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress

Nadeem, Ahmed; Al-Harbi, Naif O.; Ahmad, Sheikh F.; Alharbi, Mohammed; Alhamed, Abdullah S.; Alfardan, Ali S.; Assiri, Mohammed A.; Ibrahim, Khalid E.; Albassam, Hussam

doi:10.1016/j.intimp.2020.106369

Cited by 41 publications

(32 citation statements)

References 48 publications

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“…13,22 Th17 cells secretes various in ammatory cytokines, among which, IL-17A plays an important role in oxidative in ammation by binding to its receptors on AECII. 29 The IL-17A/IL-17RA axis has been reported to participate in several acute and chronic lung diseases. 22,30 In our study, we demonstrated that the expression of IL-17A signi cantly increased, and the level of IL-17RA on AECII increased correspondingly in the hyperoxia group.…”

Section: Discussionmentioning

confidence: 99%

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway

Guo

Zuo

et al. 2022

Preprint

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Background and Purpose: Hyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell-cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI.Methods: Mice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy (TEM). The expression of pro-inflammatory cytokine, including IL-6, TGF-β1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia.Results: Mice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-β1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively. Conclusions: IL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process.

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Section: Discussionmentioning

confidence: 99%

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway

Guo

Zuo

et al. 2022

Preprint

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“…These studies indicate that ITK inhibition may help to restore the aberrant Th17/Treg balance found in autoimmunity. In fact, some studies have already highlighted the potential for ITK inhibition to regulate Th17 and Treg function (Gomez-Rodriguez et al, 2014;Nadeem et al, 2020b). Recent whole genome sequencing of families with significant clustering of autoimmune disease has identified variants in the proximal TCR signaling pathway, including the formation of the LAT-SLP76 complex (Wang et al, 2020), further supporting the potential of ITK inhibition in autoimmune conditions.…”

Section: Autoimmune Disordersmentioning

confidence: 98%

“…This immunogenic and inflammatory environment causes a shift in the CD4 population away from Tregs and toward Th17 and Th1 cells. Clinical studies of patients with SLE and animal models of SLE have observed an increase in Th17 function and a decrease in Treg function in both serum and tissue samples (Gomez-Rodriguez et al, 2009;Nadeem et al, 2020b). In fact, several interventions aimed at restoring Th17/Treg balance in patients with SLE have proven successful, including infusions of mesenchymal stem cells (Wang et al, 2017a), autologous Treg transplantation (Dall'Era et al, 2019), and mTOR blockade (Kato and Perl, 2018).…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Targeting ITK signaling for T cell-mediated diseases

2021

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The focus of this review is to examine the role of ITK signaling in multiple diseases and investigate the clinical potential of ITK inhibition. The diseases and potential interventions reviewed include T cell-derived malignancies as well as other neoplastic diseases, allergic diseases such as asthma and atopic dermatitis, certain infectious diseases, several autoimmune disorders such as rheumatoid arthritis and psoriasis, and finally the use of ITK inhibition in both solid organ and bone marrow transplantation recipients.

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“…Both innate and adaptive immune response participate in the pathological process of ALI/ARDS [ 3 , 4 ]. Innate immune response is the first line of defense when lung injury occurs and plays a key role in regulating its excessive inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Role of Cholinergic Anti-Inflammatory Pathway in Protecting Sepsis-Induced Acute Lung Injury through Regulation of the Conventional Dendritic Cells

Chen

et al. 2022

Mediators of Inflammation

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Background. The cholinergic anti-inflammatory pathway connects the immune response system and the nervous system via the vagus nerve. The key regulatory receptor is the α7-subtype of the nicotinic acetylcholine receptor (α7nAChR). Cholinergic anti-inflammatory pathway has been proved to be effective in suppressing the inflammation responses in acute lung injury (ALI). Dendritic cells (DCs), the important antigen-presenting cells, also express the α7nAChR. Past studies have indicated that reducing the quantity of mature conventional DCs and inhibiting the maturation of pulmonary DCs may prove effective for the treatment of ALI. However, the effects of cholinergic anti-inflammatory pathway on maturation, function, and quantity of DCs and conventional DCs in ALI remain unclear. Objective. It was hypothesized that cholinergic anti-inflammatory pathway may inhibit the inflammatory response of ALI by regulating maturation, phenotype, and quantity of DCs and conventional DCs. Methods. GTS-21 (GTS-21 dihydrochloride), an α7nAchR agonist, was prophylactically administered in sepsis-induced ALI mouse model and LPS-primed bone marrow-derived dendritic cells. The effects of GTS-21 were observed with respect to maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2 (type 2 conventional DCs) and the release of DC-related proinflammatory cytokines in vivo and in vitro. Results. The results of the present study revealed that GTS-21 treatment decreased the maturation of DCs and the production of DC-related proinflammatory cytokines in vitro and in sepsis-induced ALI mouse model; it reduced the quantity of CD11c+MHCII+ conventional DCs and CD11c+CD11b+ conventional DCs2 in vivo experiment. Conclusions. Cholinergic anti-inflammatory pathway contributes to the reduction in the inflammatory response in ALI by regulating maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2.

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Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress

Cited by 41 publications

References 48 publications

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway

Targeting ITK signaling for T cell-mediated diseases

Role of Cholinergic Anti-Inflammatory Pathway in Protecting Sepsis-Induced Acute Lung Injury through Regulation of the Conventional Dendritic Cells

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