A subset of NLRs function to mitigate overzealous pro-inflammatory signaling produced by NF-κB activation. Under normal pathophysiologic conditions, proper signaling by these NLRs protect against potential #autoimmune responses. These NLRs associate with several different proteins within both the canonical and noncanonical NF-κB signaling pathways to either prevent activation of the pathway or inhibit signal transduction. Inhibition of the NF-κB pathways ultimately dampens the production of pro-inflammatory #cytokines and activation of other downstream pro-inflammatory signaling mechanisms. Dysregulation of these NLRs, including NLRC3, NLRX1, and NLRP12, have been reported in human inflammatory bowel disease ( #IBD ) and #colorectalcancer patients, suggesting the potential of these NLRs as biomarkers for disease detection. Mouse models deficient in these NLRs also have increased susceptibility to #colitis and colitis-associated colorectal cancer. While current standard of care for IBD patients and FDA-approved therapeutics function to remedy symptoms associated with IBD and chronic inflammation, these negative regulatory NLRs have yet to be explored as potential drug targets. In this review, we describe a comprehensive overview of recent studies that have evaluated the role of NLRC3, NLRX1, and NLRP12 in IBD and colitis-associated colorectal cancer.
Background
Inflammatory bowel disease (IBD) is a complex, multifactorial disorder that develops secondary to genetic, environmental, microbiological, and immunological factors [1]. IBD encompasses two chronic clinical syndromes known as Crohn’s Disease (CD) and ulcerative colitis (UC). Both variations of the disease can manifest with clinical signs that range from abdominal pain, rectal bleeding, diarrhea, and weight loss [2, 3]. CD is additionally associated with development of fistulas and rectal lesions, while pain associated with bowel movements is commonly described by UC patients [1]. Anatomically, UC is mostly limited to the colonic and rectal mucosa, whereas CD can impact any part of the GI tract [1]. However, CD is commonly localized to the ileum and colon [1]. Patients suffering from the aforementioned clinical conditions are at increased risk for the development of colorectal cancer due to the chronic inflammation associated with both disease processes [4]. IBD is characterized by immune dysregulation in the gut and is frequently associated with dysbiosis, an imbalance in commensal bacteria [5, 6].
In addition to dysbiosis, a mechanism of immune dysregulation that has been identified in IBD pathogenesis deals with pattern recognition receptors (PRRs). These are receptors found within the cell cytoplasm and lipid bilayer that are crucial for the maintenance of immune functionality in the gut. Specifically, PRRs detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to initiate downstream signaling pathways that modulate inflammation, cell death, proliferation, tissue repair and remodeling [7]. Dysregulation of PRR functionality in the GI tract commonly results in enhanced or dampened immune responses, as well as, changes in the gut microbiome leading to dysbiosis [8]. Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) are a specific group of receptors within the PRR family that are located in the cell cytoplasm that bind to PAMPs and DAMPs in the cell cytosol that also initiate or regulate downstream signaling cascades that manifest in inflammatory cytokine production [[9], [10], [11], [12]].
Both positive and negative regulatory NLRs exist, with the negative regulatory NLRs encompassing NLRC3, NLRX1 and NLRP12 [13]. The role of NLRC3 has been investigated in association with colorectal cancer tumorigenesis. Karki et al. demonstrated that mice lacking NLRC3 exhibit increased susceptibility to colorectal cancer tumorigenesis [14, 15]. Similar to NLRC3, NLRP12 also plays a critical role in protection against the development of enteritis and colitis [16]. For example, it has been demonstrated that mice lacking NLRP12 exhibit enhanced inflammatory signaling through NF-κB and ERK pathways within macrophages [17]. The dysregulation of NF-κB may be a significant factor that contributes to the development of inflammatory diseases [[18], [19], [20], [21], [22], [23]], such as colitis and colorectal cancer [[24], [25], [26]]. This relationship is important because many of the aforementioned NLRs can activate or inhibit the NF-κB signaling pathway through either the canonical or noncanonical pathway [[27], [28], [29]]. The canonical pathway contains downstream RelA (p65) and p50 heterodimers, which are regulated in the cytoplasm prior to activation by a category of inhibitors of NF-κB (IκBα). Activation of this pathway is modulated through an IκB kinase complex [30]. Within this kinase complex are IκB kinase γ, NF-κB essential modulator (NEMO) and the catalytic units IκB kinase ɑ (IKKɑ) and IκB kinase β (IKKβ) [30]. Following kinase activity, the IKK complex phosphorylates IκBα, resulting in the release of the RelA/p50 heterodimer [30]. The RelA/p50 heterodimer then translocates to the nucleus where transcription of inflammatory mediator genes occurs [30]. The canonical NF-κB pathway is responsible for modulating the inflammatory response under homeostatic conditions. Similar to the canonical pathway, a heterodimer of NF-κB is present in the form of p52 and RelB, alternative to RelA and p50, culminating in signaling via the noncanonical pathway [30]. The NF-κB-inducing kinase (NIK) is responsible for downstream modulation of p100, as liberation of NIK from its inhibitor, TRAF3, is the first step in initiating this process [30]. Once NIK is liberated into the cytosol, it phosphorylates downstream IKKα, which in turn phosphorylates and ubiquitinates p100, allowing for partial processing into p52 [30]. Following processing, p52 translocates into the nucleus with assistance from the nuclear localization sequence (NLS) to initiate gene transcription [30]. The noncanonical NF-κB pathway is relatively understudied. However, it is associated with production of cytokines associated with cancer and inflammation, recruitment of immune cells, cell proliferation, and development of secondary lymphoid structures [31].
Together, the dysregulation of canonical and noncanonical NF-κB signaling is a critical event associated with a wide range of immune mediated diseases, such as IBD. Regulatory NLRs such as NLRC3, NLRX1, and NLRP12 play critical roles in modulating NF-κB signaling (Figure 1) and have the potential to be highly relevant in the human clinic. In this review, the culmination of data from recent literature illuminates mechanisms associated with these negative regulatory NLRs in IBD and how previous work bolsters foundational data that may be useful in detecting new biomarkers and potential targets for therapeutics.
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