The MicroRNA miR-181 Is a Critical Cellular Metabolic Rheostat Essential for NKT Cell Ontogenesis and Lymphocyte Development and Homeostasis

Abstract

Regulation of metabolic pathways in the immune system provides a mechanism to actively control cellular function, growth, proliferation and survival. Here, we report that miR-181 is a non-redundant determinant of cellular metabolism and is essential to support the biosynthetic demands of early NKT cell development. As a result, miR-181-deficient mice showed a complete absence of mature NKT cells in the thymus and periphery. Mechanistically, miR-181 modulated expression of the phosphatase PTEN to control PI3K signaling, which was a primary stimulus for anabolic metabolism in immune cells. Thus miR-181-deficient mice also showed severe defects in lymphoid development and T cell homeostasis associated with impaired PI3K signaling. These results uncover miR-181 as essential for NKT cell development, and establish this family of miRNAs as central regulators of PI3K signaling and global metabolic fitness during development and homeostasis.

PTPN2 attenuates T-cell lymphopenia-induced proliferation

“…At this stage the basis for the altered PTPN2 levels during thymocyte development remain unclear. In recent years the roles of microRNAs (miRNAs) in T-cell development and CD8 þ T-cell responses have gained considerable attention 13,[54][55][56] . In particular, it has been established that miRNA-181a expression during thymocyte development is low in DN4 thymocytes, increases in DP thymocytes and then decreases again in SP thymocytes and naive T cells 13 .…”

Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation

“…Thus, miR-181 may provide excellent spatio-temporal monitoring of immune cells, modulate the strength and threshold of immune signals under physiological and pathological conditions, and switch outcomes on immune responses for tissue homeostasis. When miR-181 is deficient in a specific tissue in mice, conventional T cell and natural killer T cell development were perturbed and PI3K signaling was impaired, which results from the cumulative effect of increased PTEN expression (Henao-Mejia et al, 2013). Dan et al suggested that miR-181 upregulation is the primary host protective method against endotoxin shock, as it can switch the immune status from hyperinflammation to endotoxin tolerance by quickly decreasing inflammatory cytokine expression without influencing the expression of anti-inflammatory cytokines (Dan et al, 2014).…”

Acute Thymic Involution and Mechanisms for Recovery

“…In this investigation, miR-181-deficient mice not only exhibited a complete lack of mature NKT cells in the thymic micro-environment and periphery but also showed severe abnormalities in lymphoid growth and T cell homeostasis related to compromised phosphoinositide 3-kinase (PI3K) signaling. Mechanistically, miR-181 regulates the expression of phosphatase and tensin homolog to manage PI3K signaling, The miR-181 family is thus a fundamental regulator of universal metabolic fitness during NKT cell growth and homeostasis (Henao-Mejia et al 2013). …”