FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression.

IL-10-producing B cells (B10) are involved in the prevention of autoimmune and allergic responses but its mechanisms remain poorly understood. We took advantage of the ovalbumin-induced asthma mouse model to demonstrate that the activity of FoxO1 is upregulated in lung B cells and correlates inversely with B10 cells, while showing decreased activity in ex vivo and in vitro induced B10 cells. We further observed that FoxO1 deficiency leads to increased frequency of B10 cells. These observations have in vivo clinical evidence, as B cell specific FoxO1 deficiency leads to reduced lung eosinophils and asthma remission in mice, and there are reduced regulatory B cells and increased FoxO1 activity in B cells of asthma patients. Single cell RNA-sequencing data demonstrated a negative correlation between the expression of Foxo1 and Il10 in B cells from the mouse spleen and lung and the human lung. For a biological mechanism, FoxO1 inhibits the expression of Prdm1, which encodes Blimp-1, a transcription factor of B10 cells. Our experimental evidence in both murine and human asthma demonstrates that FoxO1 is a negative regulator of B10 cell differentiation via negatively regulating Prdm1 and its expression in B cells contributes to allergic asthma disease.

Chromatin accessibility analysis identifies the transcription factor ETV5 as a suppressor of adipose tissue macrophage activation in obesity.

Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.