NLRC5 Functions beyond MHC I Regulation—What Do We Know So Far?

Benkő, Szilvia; Kovács, Elek Gergő; Hezel, Felix; Kufer, Thomas A.

doi:10.3389/fimmu.2017.00150

Cited by 46 publications

(42 citation statements)

References 47 publications

(102 reference statements)

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“…NLRC5 is abundantly expressed in immune cells in spleen, lymph node, and bone marrow 15 . NLRC5 is also highly expressed in lung and intestine, suggesting that the functions of NLRC5 are not limited to pathogen recognition 15,16 . NLRC5 shuttles between the cytoplasm and the nucleus in a cytokine response modifier A-dependent manner and acts as a key regulator of major histocompatibility complex (MHC) class I-dependent immune responses by cooperating with regulatory factor X5 (RFX5) 17–19 .…”

Section: Introductionmentioning

confidence: 99%

NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ

Luan

Jian

et al. 2019

Nat Commun

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NLR Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation. However, the role of NLRC5 in vascular remodeling remains unknown. Here we report the role of NLRC5 on vascular remodeling and provide a better understanding of its underlying mechanism. Nlrc5 knockout ( Nlrc5 −/− ) mice exhibit more severe intimal hyperplasia compared with wild-type mice after carotid ligation. Ex vivo data shows that NLRC5 deficiency leads to increased proliferation and migration of human aortic smooth muscle cells (HASMCs). NLRC5 binds to PPARγ and inhibits HASMC dedifferentiation. NACHT domain of NLRC5 is essential for the interaction with PPARγ and stimulation of PPARγ activity. Pioglitazone significantly rescues excessive intimal hyperplasia in Nlrc5 −/− mice and attenuates the increased proliferation and dedifferentiation in NLRC5-deficient HASMCs. Our study demonstrates that NLRC5 regulates vascular remodeling by directly inhibiting SMC dysfunction via its interaction with PPARγ.

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Section: Introductionmentioning

confidence: 99%

NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ

Luan

Jian

et al. 2019

Nat Commun

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“…As mentioned above, numerous studies including our previous ones had focused on the roles of TLRs, NOD2 as well as NLRP3 in wear particles-induced osteolysis, but few studies had reported the role of USP14/NLRC5 in aseptic loosening. Besides, recent studies on NLRC5 mostly put their concentration on the relevance of NLRC5 in homeostasis and activity of CD8 T cells and natural killer (NK) lymphocytes in controlling infection and cancer [32][33][34]. Therefore, our investigation into the roles of USP4/NLRC5 of macrophages in wear particles-induced osteolysis might provide an innovative therapeutic strategy for attenuating aseptic loosening.…”

Section: Discussionmentioning

confidence: 99%

“…NOD-like receptor family CARD domain containing 5(NLRC5) is the largest member of nucleotide-binding domain and leucine-rich repeat (NLR) family, involved in various physiological processes, such as inflammation, innate immunity and diabetic nephropathy [22]. Several studies have identified NLRC5 as a negative regulator that blocks IKKα and IKKβ, two central components of the NF-κB signaling pathways and important role in homeostatic control of innate immunity [23,24].…”

Section: Introductionmentioning

confidence: 99%

The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

Fang¹,

Fu²,

et al. 2020

Journal of Biological Chemistry

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Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

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“…MHC class I and II pathways play essential roles in the activation of adaptive immune responses. Among NLRs, class II transactivator is a transcriptional coactivator that regulates IFNγ-activated transcription of MHC class I and II genes ( 42 ), whereas NLRC5 has been proven as MHC class I transactivator ( 43 ). Our previous report first identified NOD1 as a new regulator to drive the expression of MHC class I and II genes ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

RIP2 Is a Critical Regulator for NLRs Signaling and MHC Antigen Presentation but Not for MAPK and PI3K/Akt Pathways

Chen²,

et al. 2018

Front. Immunol.

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RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout in vitro. Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo. Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2. Based on our previous report and the present study, our data demonstrated that NOD1-RIP2 axis was important for larval survival in the early ontogenesis. Similar to NOD1, RIP2 deficiency significantly affected immune system processes. The significantly enriched pathways were mainly involved in immune system, such as “Antigen processing and presentation” and “NOD-like receptor signaling pathway” and so on. Furthermore, both transcriptome analysis and qRT-PCR revealed that RIP2 was a critical regulator for expression of NLRs (NOD-like receptors) and those genes involved in MHC antigen presentation. Different from NOD1, the present study showed that NOD1, but not RIP2 deficiency significantly impaired protein levels of MAPK pathways. Although RIP2 deficiency also significantly impaired the expression of CD44a, the downstream signaling of CD44a-Lck-PI3K-Akt pathway remained unchanged. Collectively, our works highlight the similarity and discrepancy of NOD1 and RIP2 in the regulation of immune signaling pathways in the zebrafish early ontogenesis, and confirm the crucial role of RIP2 in NLRs signaling and MHC antigen presentation, but not for MAPK and PI3K/Akt pathways.

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NLRC5 Functions beyond MHC I Regulation—What Do We Know So Far?

Cited by 46 publications

References 47 publications

NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ

NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ

The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

RIP2 Is a Critical Regulator for NLRs Signaling and MHC Antigen Presentation but Not for MAPK and PI3K/Akt Pathways

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