NLRP12 Regulates Immunity by Controlling Cell Migration

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  • March 22, 2019
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  • Arthur, Janelle C.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • NLRP12 is a member of the NLR family of genes that are responsible for coordinating inflammatory responses upon recognition of invading pathogens and host danger signals. Remarkably, mutations in several NLR genes have been linked to autoinflammatory diseases; greatly expanding our understanding regarding the etiology of these debilitating conditions. NLRP12 is expressed exclusively in innate immune cells and suppresses inflammation by negatively regulating the noncanonical NF-κB pathway. This is achieved by inducing proteasome-mediated degradation of NF-κB inducing kinase (NIK) in response to pathogens and activation through pro-inflammatory receptors. Because NLRP12 functions to dampen these signals, it is clear that NLRP12 must be controlled in order to mount an adequate cellular response to such insults. Here we find that NLRP12 stability is regulated by the evolutionarily conserved molecular chaperone Hsp90. In the presence of Hsp90 inhibitors, NLRP12 protein is rapidly degraded via the proteasome leading to increased NIK stability and function. Thus, Hsp90 activity is a critical regulatory factor for NLRP12 function and is required for NLRP12-induced degradation of NIK and suppression of the noncanonical NF-κB pathway. Human NLRP12 polymorphisms have been linked to atopic dermatitis and hereditary periodic fevers with skin urticaria, however the mechanisms by which NLRP12 affects these conditions remain largely unknown. To better understand these mechanisms, we tested several well defined models of inflammation using Nlrp12 knockout mice. Remarkably, we found that Nlrp12 deficient mice failed to mount T cell mediated responses in hapten induced contact hypersensitivity, a model of allergic dermatitis, and EAE, a model of multiple sclerosis. Mechanistically this is due to defective migration of peripheral dendritic cells. These innate immune cells express Nlrp12 and play a pivotal role in T cell activation. Molecular analysis reveals that in the absence of NLRP12, dendritic cells display an inappropriate activation of NIK, resulting in high levels of NIK dependent gene expression. These findings expand our understanding of NLRP12 function in vivo and provide a rationale for the diseases associated with this NLR. Furthermore our results reveal a novel role for NLRP12 in bridging innate and adaptive immunity.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology
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  • Ting, Jenny P.-Y.
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