The inflammatory response to anything that appears dangerous to the integrity of an organism is a highly evolved and complex biological reaction that requires the orchestrated action of numerous cell types mediated by a continuous flow of extracellular cues in the form of cytokines and other messengers. Too little or too much activation of this response can have dire consequences for the organism, as exemplified by a wide spectrum of hematopoietic disorders - from cancer to autoimmunity. The precise execution and coordination of different steps during inflammation requires the activation of intricate genetic programs that are driven by a myriad of cell surface receptors and transcriptional factors.
Until recently, the complexity of gene regulation during the innate immune response was considered only from the perspective of protein-coding genes. However, the discovery of miRNAs and the advent of high-throughput sequencing technologies have revolutionized our understanding of gene control. It is apparent today that the human genome is pervasively transcribed and produces a staggering number of non-protein-coding transcripts, including miRNAs, siRNAs, piRNAs and long noncoding RNAs. These RNA molecules operate as key regulators of other functional elements in the genome, especially protein-coding genes, and are known to control diverse biological processes. Understanding the biology and molecular mechanism of action of noncoding RNAs that govern development and functioning of immune system is the long-term goal of our laboratory.
A few years ago, we hypothesized that miRNAs might comprise a novel layer of regulation of the innate immune response and have carried out a systematic effort to identify miRNAs that might be involved in the mammalian response to microbial infection. We identified three miRNA genes (miR-146a, miR-132 and miR-155), whose expression is sharply upregulated in response to bacterial lipopolysaccharides (LPS) and studied the function of one of them, miR-146a, in depth.
Using loss-of-function genetic approach, we found that miR-146a functions as a key molecular brake on inflammation and cancer. Deletion of this miRNA gene results in the development of autoimmune disease and frank tumors of hematopoietic origin. Our initial molecular studies suggest that this miRNA acts as a negative feedback regulator of the innate immune response by silencing expression of two adapter proteins, TRAF6 and IRAK1, which are critical for multiple aspects of proinflammatory and antigen receptor signaling.
Current research in our laboratory is defining the contribution of both small and long noncoding RNAs to the regulation of gene expression during development and functioning of the immune system. Besides being fundamentally important, this work can potentially shed light on how dysregulation of immune cell signaling can result in autoimmunity and cancer and could lead to the creation of new therapeutic modalities to fight these devastating diseases.