IRF4 and STAT3 Play a Role in the Imbalanced Differentiation of T-Cells in Responses to Inhalable Particulate Matters in Human

Background: Particulate Matter (PM) is known to cause inflammatory responses in human. Although prior studies verified the immunogenicity of PM in cell lines and animal models, the effectors of PM exposure in the respiratory system and the regulators of the immunogenicity of PM is not fully elucidated. Methods: We performed gene-expression profiling of peripheral blood mononuclear cells from 171 healthy subjects in northern China to identify co-expressed gene modules associated with PM exposure. We inferred transcription factors regulating the co-expression and validated the association to T-cell differentiation in both primary T cells and mice treated with PM. Findings: We report two transcription factors, IRF4 and STAT3, as regulators of the gene expression in response to PM exposure in human. We confirmed that the activation of IRF4 and STAT3 by PM is strongly associated with imbalanced differentiation of T-cells in the respiratory tracts in a time-sensitive manner in mouse. We also verified the consequential inflammatory responses of the PM exposure. Moreover, we show that the protein levels of phosphorylated IRF4 and STAT3 increase with PM exposure. Interpretation: Our study suggests IRF4 and STAT3 are potential effectors of PM exposure and regulators of the inflammation in the respiratory tracts. Funding Statement: Natural Science Foundation of Fujian Province (No. 2016J01644), National Natural Science Foundation of China (No. 31371289), and Science and Technology Bureau of Xiamen (NO. 3502Z20189013). Declaration of Interests: The authors declare no competing financial interests. Ethical Approval Statement: This study protocol and informed consent form were overseen and approved by a steering committee, institutional review boards of Xiamen University and the First Affiliated Hospital of Xiamen University. All methods were carried out in accordance with the relevant guidelines and regulations.