Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Airway Neutrophilia.

Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with TH17 responses. However, how UPRs participate in the deregulation of TH17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

Unfolded protein response factor ATF6 augments T helper cell responses and promotes mixed granulocytic airway inflammation.

The unfolded protein response (UPR) is associated with the risk of asthma, including treatment-refractory severe asthma. Recent studies demonstrated a pathogenic role of activating transcription factor 6a (ATF6a or ATF6), an essential UPR sensor, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by signal transducer and activator of transcription6 (STAT6) and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed the expression of ATF6 downstream genes and TH cell cytokines by both murine and human memory clusters of differentiation 4 (CD4)+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.

Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Neutrophilic Airway Inflammation.

Treatment-refractory severe asthma manifests a neutrophilic phenotype associated with TH17 responses. Heightened unfolded protein responses (UPRs) are associated with the risk of asthma, including severe asthma. However, how UPRs participate in the deregulation of TH17 cells leading to this type of asthma remains elusive. In this study, we investigated the role of the UPR sensor IRE1 in TH17 cell function and neutrophilic airway inflammation. We found that IRE1 is induced in fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a Candida albicans asthma model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPRmediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

Accumulation of CD28null Senescent T-Cells Is Associated with Poorer Outcomes in COVID19 Patients.

Coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes infectious disease, and manifests in a wide range of symptoms from asymptomatic to severe illness and even death. Severity of infection is related to many risk factors, including aging and an array of underlying conditions, such as diabetes, hypertension, chronic obstructive pulmonary disease (COPD), and cancer. It remains poorly understood how these conditions influence the severity of COVID-19. Expansion of the CD28null senescent T-cell populations, a common phenomenon in aging and several chronic inflammatory conditions, is associated with higher morbidity and mortality rates in COVID-19. Here, we summarize the potential mechanisms whereby CD28null cells drive adverse outcomes in disease and predispose patients to devastating COVID-19, and discuss possible treatments for individuals with high counts of CD28null senescent T-cells.