Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals

Wang, Chun; Hockerman, Susan; Jacobsen, E. J.; Alippe, Yael; Selness, Shaun R.; Hope, Heidi R.; Hirsch, Jeffrey L.; Mnich, Stephen J.; Saabye, Matthew J; Hood, William F.; Bonar, Sheri L.; Abu‐Amer, Yousef; Haimovich, Ariela; Hoffman, Hal M.; Monahan, Joseph B.; Mbalaviele, Gabriel

doi:10.1084/jem.20172063

Cited by 75 publications

(76 citation statements)

References 51 publications

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“…Previous studies showed that MAPK-MAPK (MK2) is down-stream of p38 MAPK, and that MK2 mediates inflammatory responses. 24,25 Addition of a specific MK2 inhibitor (MK2 IV) to NK-cell cultures diminished the enhancing effect of IL-33 on IL-12-stimulated IFNproduction ( Fig. 8).…”

Section: Mapk-mapk Contributes To Il-33 Enhancement Of Il-12-induced mentioning

confidence: 93%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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Section: Mapk-mapk Contributes To Il-33 Enhancement Of Il-12-induced mentioning

confidence: 93%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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“…Nlrp3 inflammasome signaling is postulated to play a role in a growing array of inflammatory diseases, ranging from IBD, 79 rheumatic diseases, 80 and pancreatitis 81 to the neurodegenerative disorder Alzheimer's disease 82 . This renders it a promising therapeutic target 25 .…”

Section: Nod‐like Receptor Familymentioning

confidence: 99%

The microbiome and cytosolic innate immune receptors

Liwinski

Zheng

Elinav

2020

Immunological Reviews

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The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune‐mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host‐environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide‐binding domain, leucine‐rich repeat‐containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid‐inducible gene‐I (RIG‐I)–like receptors (RLRs), cyclic GMP‐AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host‐microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

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“…Unexpectedly, conditional activation of NLRP3 in myeloid cells but not in osteochondro-progenitors reproduces the abnormal cartilage features, suggesting that the phenotype is not chondrocyte autonomous [75]. CAPS mice also exhibit severe low bone mass, a phenotype that correlates with a massive expansion of osteoclast precursors, exuberant osteoclastogenesis, and increased osteoclast activity [41,73,[75][76][77]. Thus, while the magnitude of bone resorption in CAPS patients is not known, this process is prominent and well characterized in mouse models.…”

Section: Cryopyrin-associated Periodic Syndromesmentioning

confidence: 99%

“…Irrespective of the hierarchy of the events, IL-1β and its effectors act in synergy with RANKL to promote osteoclast differentiation and activity while suppressing osteogenesis [32]. IL-1β also stimulates its own synthesis, a positive feedback mechanism that underlies the chronicity of inflammasome actions in bone diseases [33,41]. On the other hand, while pro-inflammatory actions of IL-18 in skin disorders [42] and infection-associated allergic diseases [43] are well described, the role of this cytokine in bone is ambiguous.…”

Section: Secondary Signalsmentioning

confidence: 99%

Omnipresence of inflammasome activities in inflammatory bone diseases

Alippe

Mbalaviele

2019

Semin Immunopathol

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The inflammasomes are intracellular protein complexes that are assembled in response to a variety of perturbations including infections and injuries. Failure of the inflammasomes to rapidly clear the insults or restore tissue homeostasis can result in chronic inflammation. Recurring inflammation is also provoked by mutations that cause the constitutive assembly of the components of these protein platforms. Evidence suggests that chronic inflammation is a shared mechanism in bone loss associated with aging, dysregulated metabolism, autoinflammatory, and autoimmune diseases. Mechanistically, inflammatory mediators promote bone resorption while suppressing bone formation, an imbalance which over time leads to bone loss and increased fracture risk. Thus, while acute inflammation is important for the maintenance of bone integrity, its chronic state damages this tissue. In this review, we discuss the role of the inflammasomes in inflammation-induced osteolysis.

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Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals

Abstract: A unique p38α MAPK–MK2 pathway inhibitor, CDD-450, is used to uncover the function of this protein complex in inflammasome priming signals. Importantly, CDD-450 is as efficacious as global p38α MAPK inhibitors in decreasing inflammation in disease models.

Cited by 75 publications

References 51 publications

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

The microbiome and cytosolic innate immune receptors

Omnipresence of inflammasome activities in inflammatory bone diseases

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