Cutting Edge: NLRP12 Controls Dendritic and Myeloid Cell Migration To Affect Contact Hypersensitivity

Arthur, Janelle C.; Lich, John D.; Ye, Zhengmao; Allen, Irving C.; Gris, Denis; Wilson, Justin E.; Schneider, Monika; Roney, Kelly E.; O’Connor, Brian P.; Moore, Chris B.; Morrison, Amy C.; Sutterwala, Fayyaz S.; Bertin, John; Koller, Beverly H.; Li, Zhi; Ting, Jenny P.Y.

doi:10.4049/jimmunol.1002227

Cited by 140 publications

(181 citation statements)

References 22 publications

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“…For instance, it has been shown that ASC and NLRP3 deficient mice display an impaired response to the skin sensitizers DNFB and TNCB (Watanabe et al, 2007). More recently, it was found that the LC of NLRP12 −/− mice exhibit defective migration to draining LN (Arthur et al, 2010). In this latter study, it was found also that NLRP12 deficiency attenuates the inflammatory response in two separate models of skin sensitization.…”

Section: The Integral Inflammasomesupporting

confidence: 58%

“…As the negative regulation of IL-1β by NLRP12 would effectively inhibit LC migration and DC accumulation, the presumption is that this mechanism would prevent the acquisition of skin sensitization. However, as NLRP12 is known to be required for the development of skin sensitization to certain allergens, it is postulated that there must be some, as yet unknown mechanism for the observed dependence upon NLRP12 (Arthur et al, 2010).…”

Section: Nlrp12mentioning

confidence: 99%

See 1 more Smart Citation

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Ainscough

Gerberick

Dearman

et al. 2012

Journal of Immunotoxicology

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Section: The Integral Inflammasomesupporting

confidence: 58%

Section: Nlrp12mentioning

confidence: 99%

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Ainscough

Gerberick

Dearman

et al. 2012

Journal of Immunotoxicology

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“…Other NLR family members have been suggested to regulate DC maturation or migration, such as NLRP3 and NLRP12, respectively (17,18). The mechanisms by which these NLRs regulate DC function have not been determined.…”

Section: Resultsmentioning

confidence: 99%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

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“…Elevated local or systemic levels of IL-1β, associated with inappropriate inflammasome activity, have been reported in various diseases, particularly in allergic disorders (10)(11)(12). Furthermore, previous studies have reported that NLRP3, NLRP12 and absent in melanoma (AIM)2 are involved in different models of allergy (13)(14)(15). In addition, NLRP3 has been introduced as an important inflammasome in contact hypersensitivity (16) and allergic airway diseases (14,17).…”

Section: Elevated Caspase-1 Activity and Il-1β Expression Are Associamentioning

confidence: 99%

Elevated caspase-1 activity and IL-1β expression are associated with the IPAF inflammasome in an experimental model of allergy

Nouri

Karkhah

Mohammadzadeh³

et al. 2016

Molecular Medicine Reports

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Abstract. Previous studies have indicated that interleukin (IL)-1β has an important role in the development of allergic diseases. Therefore, the present study aimed to investigate the upstream pathway underlying IL-1β production in an experimental model of allergy. BALB/c mice (female, 6-8 weeks old) were sensitized to recombinant (r) Che a 2 by intraperitoneal injection of rChe a 2 adsorbed onto an alum gel suspension on days 0, 7, 14 and 21. In the control group, mice received an injection of 20 mM phosphate-buffered saline absorbed onto alum via the same route. The allergic status of the mice was confirmed serologically by measuring allergen-specific immunoglobulin (Ig)E levels. The protein expression levels of IL-1β and the mRNA expression levels of inflammasome compartments were measured by enzyme-linked immunosorbent assay and semi-quantitative reverse transcription polymerase chain reaction, respectively. In addition, caspase-1 activity was determined by fluorometric assay. Sensitized mice exhibited significantly increased levels of specific IgE (P<0.05). IL-1β production and caspase-1 activity were significantly higher in the sensitized mice compared with the control group. In addition, no significant differences were observed between the control and sensitized mice in the expression of genes associated with the inflammasome, including NLR family, pyrin domain containing 3; apoptosis-associated speck-like protein; and NLR family, apoptosis inhibitory protein 5. However, IL-1β converting enzyme protease-activating factor (IPAF) expression was significantly increased in sensitized mice compared with in the control group (P<0.05). These data indicate that caspase-1 activation and IL-1β expression are associated with the IPAF inflammasome. Therefore, based on this association, the IPAF inflammasome may be considered for IL-1β production in the experimental model of allergy. IntroductionAn allergic response is characterized by an exaggerated immune reaction to certain antigens, including harmless environmental antigens from various sources, such as food and pollen. Approximately 25% of the population in developed countries suffers from immunoglobulin (Ig)E-mediated type I allergy (1,2). Interleukin (IL)-1β has been identified as an important cytokine, which has a key role in the pathophysiology of allergic disorders (3). Furthermore, IL-1β has an essential role in the immune response to infectious agents (4).IL-1β can be produced by immune cells, including blood monocytes, tissue macrophages and dendritic cells (5). IL-1β secretion is a two-step process: Firstly, interaction of Toll-like receptors (TLRs) with their ligands leads to an upregulation of pro-IL-1β gene transcription via nuclear factor-κB (6). Secondly, caspase-1 activation results in the conversion of the immature pro-IL-1β into mature IL-1β. It is well-established that caspase-1 activity is regulated by a cytosolic multi-protein complex known as the inflammasome (7). The inflammasome consists of a nucleotide-binding domain like receptor (NLR), o...

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Cutting Edge: NLRP12 Controls Dendritic and Myeloid Cell Migration To Affect Contact Hypersensitivity

Cited by 140 publications

References 22 publications

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Elevated caspase-1 activity and IL-1β expression are associated with the IPAF inflammasome in an experimental model of allergy

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