The NLR family pyrin domain–containing 11 protein contributes to the regulation of inflammatory signaling

Abstract

Mammalian 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 analysed 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 signalling pathways including NF-κB and type I interferon responses. NLRP11 harbours a pyrin domain (PYD), which is responsible for inflammasome formation in related NLR proteins. However, NLRP11 did neither interact with the inflammasome adaptor protein ASC nor did it 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 PYD domain and ATPase activity of NLRP11. SiRNA-mediated knock-down of NLRP11 in human myeloid THP1 cells validated these findings and revealed enhanced lipopolysaccharide (LPS) and Sendai Virus (SeV)-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.An inflammatory response is triggered in response to cell damage and to defend against invading pathogens. In mammals, this is mediated by the activation of cellular pathways cumulating into the release of cytokines, chemokines and interferons. Downstream, this orchestrates recruitment of effector cells, alerts a systemic response and restores tissue homeostasis (1). Activation of pattern-recognition receptors (PRRs 2 ), expressed in and on host cells, which respond towards pathogen-derived substances, cell damage and stress, initiate this response. On the cellular level, inflammation is mediated by the activation of proinflammatory signaling cascades such as the activation of caspase-1, NF-κB, IRFs, amongst others. Chronic In humans, the TLR, NLR and C-type lectin family members are the most relevant PRRs. Many mammalian NLR proteins have been associated with multiple functions in inflammation and innate and adaptive immune responses (4) and dysfunctions in NLRs are associated with a range of diseases including Crohn's disease, periodic fever syndromes and Blau Syndrom (5), highlighting their physiologic relevance NLR proteins have a typical tripartite domain architecture and can be classified functionally according to their N-terminal domain which is, in most cases a CARD or PYD domain (6). Most but not all PYD-containing NLRs can interact with the adaptor molecule ASC to form high molecular weight complexes in cells, referred to as inflammasomes, which function as a platform for the activation of caspase-1 and subsequent IL-1β and IL-18 processing. The NLR family-member pyrin domain-containing protein 11 (NLRP11, NALP11, NOD17, PYPAF6, PAN...

Different Intensity Exercise Preconditions Affect Cardiac Function of Exhausted Rats through Regulating TXNIP/TRX/NF-ĸBp65/NLRP3 Inflammatory Pathways

“…Feriani et al found significant improvement in inflammatory parameters and cardiac function indicators in exhausted rats after aerobic exercise training. In order to control the harmful effects of inflammation on cardiac function, we need to pay more attention to the regulation of inflammatory pathways and strictly control inflammatory pathways and their activators [34,35].…”

Adenosine-Induced NLRP11 in B Lymphoblasts Suppresses Human CD4+ T Helper Cell Responses

“…Earlier characterization studies on NLRP11 reported that NLRP11 does not colocalize with ASC in 293T cells [30]. Furthermore, NLRP11 does not associate with ASC in transiently transfected living HeLa cells [3]. Hence, we assessed the impact of adenosine activation on NLRP11 and ASC protein interaction by coimmunoprecipitation (Figure 3(a)).…”

“…NLRs are grouped into four structurally similar subfamilies, namely, NLRA, acidic domain containing; NLRB, baculoviral inhibitory repeat (BIR) domain containing; NLRC, caspase activation and recruitment domain (CARD) containing; and NLRP, pyrin domain (PYD) containing, as well as, NLRX, which has no significant homology to the N-terminal domain of any other member of the NLR subfamily [ 2 ]. Although NLRP11 is commonly considered a primate-specific NLR [ 3 ], rabbits, placentals, bats, pigs, and lemurs also express different isoforms of NLRP11 with amino acid sequence identities ranging from 45.6% to 58.6%. Additionally, sequence comparison analysis revealed that human NLRP11 has the closest amino acid sequence identity to NLRP4 of the nonprimate species Tupaia chinensis (36%) and Mus musculus (33.5%).…”

Negative Regulation of Cytosolic Sensing of DNA

“…In addition, NLRC5 can suppress TLR signaling by modulating IKK activation (Cui et al, 2010), though NLRC5 deficiency does not affect this signaling pathway (Kumar et al, 2011b). Finally, the primate specific NLRP11 suppresses TLR-mediated activation of NF-κB by targeting TRAF6 for degradation in myeloid cells and B-cells (Ellwanger et al, 2018;Qin et al, 2017b;Wu et al, 2017). Together, these emerging properties call into question whether the established role for this family in activating proinflammatory responses may in fact represent an exception rather than a rule.…”