Elucidating the contribution of PRRs in inflammatory diseases is an essential pillar of my laboratory.
Inflammatory bowel disease (IBD)
My research program is focused primarily on mechanisms associated with mucosal inflammatory diseases, such inflammatory bowel disease (IBD). Over the last 6 years, we have made significant progress in this field. Crohn's disease and ulcerative colitis are common and debilitating manifestations of IBD. Together, these two disorders afflict approximately 1.4 million Americans and over 4 million people worldwide.
IBD is considered to be an autoimmune disease that is characterized by an imbalance of pro-inflammatory and anti-inflammatory signaling pathways in the gastrointestinal system. My team’s work in this field generated some of the first studies to associate PRRs with protective roles in disease pathobiology.
"NOD-like" receptors (NLRs) in IBD
When we first began exploring the NLR family in IBD, we hypothesized that attenuation of the pro-inflammatory NLRs and associated pathways would attenuate disease pathogenesis. However, our findings surprisingly revealed that these pro-inflammatory proteins are actually essential in maintaining immune system homeostasis in the gut and removing any of these proteins actually worsens disease progression, suggesting that they actually play a vital protective role in the gut. Together, our work suggests that each NLR attenuates IBD through cell type, temporal, and stimuli specific mechanisms in response to specific elements of the host microbiome.
This line of research has resulted in publications in several high profile journals, including The Journal of Experimental Medicine (IF: 14.10), Inflammatory Bowel Diseases (IF: 5.475) and The Journal of Immunology (5.67).
NLRP12 in IBD
In addition to the pro-inflammatory sub-group of NLRs, I was also one of the first people to identify a role for the anti-inflammatory NLR NLRP12 in IBD. This unique NLR functions through the negative regulation of NF-κB signaling. NF-κB is a master regulator of gene transcription and is a critical modulator of the immune response. NF-κB signaling is divided into 2 distinct cascades, termed the canonical pathway and non-canonical pathway. My research revealed a role for NLRP12 modulation of the non-canonical NF-κB signaling pathway in disease pathogenesis. This is a very unique finding and resulted in a publication in the journal Immunity (IF: 20.72).
These findings were also the basis for a successfully funded NIH R03 grant and a series of internal IRC grants to better evaluate the role of PRRs in the modulation of inflammatory signaling pathways.
Together, the work from my research teams in these areas of study have resulted in a paradigm shift in the way we think about not only NLRs, but also other PRRs, pro-inflammatory cytokines and signaling pathways in the gut and identified protective roles for the NLR family in not only IBD, but a range of other inflammatory diseases. We are now exploring the contribution of not only NLRs, but also other PRRs in other inflammatory diseases beyond IBD. We are also translating these findings from bench-to-bedside by elucidating methods to target PRR signaling pathways with novel therapeutic approaches.
There is an intimate link between inflammation and tumorigenesis. Nowhere is this more apparent than in the context of IBD and colon cancer. While the association is clear, the mechanism is not well understood. For example, which comes first, inflammation or cancer?
To address some of the fundamental questions associated with tumor immunology, our laboratory is currently utilizing both common and novel models of inflammation driven tumorigenesis in the gut. We are continuing to focus on the contribution of the PRRs in these processes.
Our current work is associated with both NLR and TLR modulation of tumorigenesis. As with IBD, my early work in this field generated some of the first studies to associate NLR proteins with epithelial cell barrier function and the attenuation of tumorigenesis in the gut. Indeed work conducted since arriving at Virginia Tech and published in American Journal of Physiology-GLP (IF: 3.853) and The Journal of Immunology (5.570) has revealed that each NLR appears to attenuate tumorigenesis, likely through cell type, temporal, and stimuli specific mechanisms associated with recognition of atypical components of the host microbiome.
We are now extending these findings to regulators of the TLR and RLR families and exploring the contribution of these PRRs in other cancer models with a connection to aberrant immune system function, including lung cancer and breast cancer.
The PRRs were originally identified due to their role in initiating the host innate immune response following pathogen exposure. My earliest work in the NLR field focused on the contribution of both inflammasome forming NLRs and regulatory NLRs in host-pathogen interactions.
Many of my original publications in this field were some of the first studies evaluating the physiological and clinical contribution of NLRs following pathogen exposure using genetically modified mice. For example, my work with influenza virus and inflammasome forming NLRs was published in Immunity (IF: 20.72) and underlie the current paradigm of NLR function, whereby pathogens are sensed at early time-points of infection resulting in NLR signaling activation and subsequent optimization of host-pathogen immune responses.
Subsequent studies using a diverse range of viruses and bacteria have been essential in elucidating mechanistic insight associated with unique members of the NLR family. For example, I published the first in vivo study associated with NLRX1, which is a member of a novel sub-group of NLRs. I am the first author on this manuscript, which is the original paper characterizing NLRX1 in the mouse (Immunity; IF: 20.72).
Likewise, I am either the author or a co-author on the first papers published describing the roles of the related NLRs, NLRP12 (The Journal of Immunology; IF: 5.67) and NLRC3 (Nature Immunology; IF: 26.20), which also function as negative regulators of inflammation in the mouse following exposure to pathogens. These proteins function through the regulation of signaling cascades driven by other classes of PRRs, including the TLRs and RLRs.
We are continuing to study the role of the inflammasome forming NLRs and regulatory NLRs in a variety of pathogen models. Likewise, we are also studying the contribution of these proteins and the signaling pathways they modify in the recognition of components of the host microbiome in support of the inflammatory disease and cancer research focus areas.