Abstract
Mammalian Nod-like receptor (NLR) proteins contribute to the regulation and induction of innate and adaptive immunity in mammals, although the function of about half of the currently identified NLR proteins remains poorly characterized. Here we analyzed the function of the primate-specific NLRP11 gene product. We show that NLRP11 is highly expressed in immune cells, including myeloid cells, B cells, and some B cell lymphoma lines. Overexpression of NLRP11 in human cells did not trigger key innate immune signaling pathways, including NF-κB and type I interferon responses. NLRP11 harbors a pyrin domain, which is responsible for inflammasome formation in related NLR proteins. However, NLRP11 did not interact with the inflammasome adaptor protein ASC, and it did not trigger caspase-1 activation. By contrast, expression of NLRP11 specifically repressed NF-κB and type I interferon responses, two key innate immune pathways involved in inflammation. This effect was independent of the pyrin domain and ATPase activity of NLRP11. siRNA-mediated knockdown of NLRP11 in human myeloid THP1 cells validated these findings and revealed enhanced lipopolysaccharide and Sendai virus-induced cytokine and interferon responses, respectively, in cells with reduced NLRP11 expression. In summary, our work identifies a novel role of NLRP11 in the regulation of inflammatory responses in human cells.
Highlights
Mammalian Nod-like receptor (NLR) proteins contribute to the regulation and induction of innate and adaptive immunity in mammals, the function of about half of the currently identified NLR proteins remains poorly characterized
The Burkitt’s B cell lymphoma line Daudi expressed the highest levels of NLRP11 mRNA, and robust expression was seen in myeloid THP1 cells, whereas epithelial cell lines expressed low levels of NLRP11 (Fig. 1B)
Analysis of gene chip data showed that, among different tumor entities, NLRP11 was highest expressed in diffuse large B cell lymphoma, hepatocellular carcinoma, and Burkitt’s lymphoma (Fig. S1B)
Summary
We experimentally determined the expression pattern of NLRP11. Quantitative RT-PCR from human tissues revealed high expression of NLRP11 mRNA in the testis, ovary, and liver (Fig. 1A, left panel), in line with expression data deposited at the GTex portal (Fig. S1A). In contrast to other NLRs, such as NLRC5, CIITA, Nod, and Nod, which trigger specific cellular signaling pathways upon their overexpression in this system, ectopic expression of NLRP11 did not significantly activate promoters responsive to major histocompatibility complex class I and II, NF-AT, SMAD, IFN, or NF-B (Fig. 3A). Our data above suggest that NLRP11 targets effectors involved in pathways downstream of TLR4 and TBK1 To define these factors, we tested the effect of NLRP11 overexpression on NF-B responses induced by overexpression of TNF receptor–associated factors (TRAFs), which differentially contribute to both pathways, with TRAF6 mainly contributing to MyD88-dependent responses and TRAF2 mediating TNFinduced responses [26].
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