Allen Laboratory: Research Interests

Inflammatory Disease

Elucidating the contribution of PRRs in inflammatory diseases is an essential pillar of my laboratory. Since our laboratory's inception, we have made significant progress in this field. My team's work generated some of the first studies to associate PRRs with protective roles in respiratory and gastrointestinal disease pathobiology. For example, when we first began exploring the NLR family in inflammatory bowel disease (IBD), we hypothesized that blocking 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. 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. 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 mucosal tissues. Based on these studies, we have begun expanding our research program beyond the mucosa and applying our findings to other organ systems and in the context of a variety of inflammatory disease and damage associated injury models.

The Goldilocks Conundrum

The Goldilocks Conundrum: NLR Inflammasome Modulation of Gastrointestinal Inflammation during Inflammatory Bowel Disease. Ringel-Scaia VM, McDaniel DK, Allen IC. Crit Rev Immunol. 2016;36(4):283-314. doi: 10.1615/CritRevImmunol.2017019158. Review.

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Top Image: Normal Mammary Gland with Lymphnode
Bottom Image: Mammary Tumor Infiltrating Lymphnode

Tumor Immunology

There is an intimate link between dysregulated 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. We are continuing to focus on the contribution of the innate immune system and PRRs in these processes.

This line of research has resulted in publications in several high profile journals, including The Journal of Experimental Medicine (IF: 14.10) and The Journal of Immunology (IF: 5.67). In addition to the pro-inflammatory sub-groups of PPRs, I was also one of the first people to identify a role for the negative regulatory NLR NLRP12 in inflammation driven tumorigenesis. 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). Our current work is associated with both NLR and TLR modulation of tumorigenesis. Indeed, work recently published in The Journal of Immunology (IF: 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 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.

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Host-Microbe Interactions

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.

Indeed, 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 act 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.

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Pre-Clinical Animal Models

The translation of basic research principles from "bench-to-bedside" is another major focus of my research team. My group has participated in several highly interdisciplinary collaborations with clinicians, engineers, and basic scientists to assist them in translating their novel ideas and concepts into viable treatment strategies targeting a diverse range of infectious diseases, immune system disorders, and cancer. We have developed a wide range of novel in vitro, ex vivo, and/or in vivo models, which have played essential roles in evaluating the technology or approach of interest. These interdisciplinary collaborations are often highly challenging, but also highly rewarding for both me and my research team.

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