NLRs: Sentinels of innate immunity or cancer culprits?

The intersections between innate immunity and cancer have been investigated for decades, with widespread acceptance that chronic inflammation contributes to the pathogenesis or progression of several types of malignancies. Numerous mediators of innate immune responses have been connected to tumor risk through genetic, molecular, and cellular analysis [1]. The NACHT and Leucine Rich Repeat domain containing proteins (NLRs) represent a family of innate immunity proteins responsible for pathogen sensing in the cytosol. Analogous to membrane-associated Toll-like receptors (TLRs), there is evidence that NLRs participate in recognition of both pathogen-associated molecular patterns (PAMPs) and endogenous byproducts of tissue injury (danger associated molecular patterns, DAMPs) [1, 2]. NLRs activate inflammatory signaling pathways including NF-κB and MAPK, stress kinases, interferon responses factors (IRFs), autophagy, and caspasedependent cytokine secretion. A growing body of evidence has associated NLR polymorphisms with several human cancers. However, the precise role of these NLRs in cancer progression is not well defined. To date, a total of 22 NLRs have been described in humans, but this number rises when considering atypical members that possess alternate domain structures. Currently, a basic characterization of all NLR members is lacking, thus our insights into the diversity of activators of these proteins and the downstream signaling pathways they control are limited to a few of the family members. The most studied NLRs include NOD1 (NLRC1) and NOD2 (NLRC2), which are responsible by the activation of innate immunity signaling pathways through recognition of particular bacterial peptidoglycan derivatives. NOD activation is driven by NACHT domain-mediated self-oligomerization and by CARD-CARD interactions with downstream effectors, including RIP2, which recruits TAB/TAK complexes to activate IκB kinase complex (IKK) and MAPK kinases, resulting in NF-κB and AP-1 signaling activation, respectively [2]. NOD1 and NOD2 have both been defined as seminal players in gut homeostasis, providing protection against colitis and cancer. Indeed, Nod1-/mice show remarkable predisposition for tumor formation using a colitis-associated colon cancer model [3]. Also, breast cancer cells (MCF-7) devoid of NOD1 expression give rise to larger tumors after injection in immunocompromised (SCID) mice [4]. More recently, NOD2 gene polymorphisms have been associated with higher predisposition to a number of cancer types, including increased risk of gastric cancer in H. pyloriinfected patients [5]. These observations have prompted several investigators to consider NODs as possible therapeutic targets for pro-inflammatory diseases and Editorial Material