Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Abstract

Background: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 mm or less in diameter (PM2.5) aggravates asthma. Objective: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. Methods: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4 1 T cellspecific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of T H 17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. Results: PM2.5 impaired differentiation of Treg cells, promoted differentiation of T H 17 cells, and aggravated asthma in an AhRdependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of T H 17 cells by upregulating hypoxia-inducible factor 1a expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of T H 17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on T H 17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. Conclusions: The AhR-hypoxia-inducible factor 1a and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of T H 17/Treg cells.

Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis

“…The effects of Sema4D are believed to be regulated via three receptors: Plexin B1, Plexin B2, and CD72 ( 33 ). The effects of Sema4D are believed to be regulated via three receptors:PlexinB1,PlexinB2, and CD72 ( 32 – 34 ). To determine which receptor is involved in the stimulatory effect of Sema4D observed in CD4 + T cells, we first used qRT-PCR to evaluate the transcription of Plexin B1, Plexin B2, and CD72 in CD4 + T cells derived from patients with AS and healthy subjects.…”

“…Recently, an increasing number of reports have elicited that AhR playes a critical role in the regulation of Th17 and Treg cell differentiation (12,32). Thus, we investigated whether AhR contributes to the Sema4D-mediated the balance of Th17/Treg cells, CD4 + T cells were transfected with siAhR in the presence of Sema4D under Th17-or Treg-polarizing conditions, and the expression levels of AhR and the AhR target gene CYP1A1 were measured.…”

Semaphorin 4D induces an imbalance of Th17/Treg cells by activating the aryl hydrocarbon receptor in ankylosing spodylitis

“…Recently, an increasing number of reports have elicited that AhR played a critical role in the regulation of Th17 and Treg cell differentiation [31,32]. Thus, we investigated whether AhR contributes to the Sema4D-mediated the balance of Th17/Treg cells, CD4+ T cells were incubated with or without Sema4D under Th17 or Treg cell polarization conditions.…”

Idiopathic Membranous Nephropathy: Glomerular Pathological Pattern Caused by Extrarenal Immunity Activity

“…The exposure of autoantigens then aggravates the local inflammation, which leads to the formation of a vicious circle (105). Under the stimulation of environmental factors, the function of immune cells will also be affected, such as the auto-reactive T cells and the antigen presenting cells, thus increasing the risk of loss of self-tolerance abilities (106,107). This will subsequently induce the humoral immunity targeted to the extrarenal auto-antigen (PLA2R1 or THSD7A), which is programed to control the local inflammation and tissue damage.…”