p38γ and p38δ: From Spectators to Key Physiological Players

Cuenda, Ana; Sanz‐Ezquerro, Juan José

doi:10.1016/j.tibs.2017.02.008

Cited by 73 publications

(106 citation statements)

References 71 publications

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“…The redundant, distinct and even opposing functions of each p38 isoform have been reported (25,49). p38 and p38, referred to as the conventional p38 isoforms, have been studied more extensively, while the specialized functions of p38 and p38, known as the alternative p38 isoforms, are less understood, in part, due to the lack of inhibitors specific to these isoforms (7).…”

Section: Introductionmentioning

confidence: 99%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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BACKGROUND: The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38 and p38, remain uncharacterized. OBJECTIVES: To determine the potential cardioprotective effects of p38 and p38 genetic deletion in mice subjected to acute DOX treatment. METHODS: Male and female wild-type (WT), p38 -/-, p38 -/-and p38 -/- -/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining.Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: Significantly improved survival was observed in p38 -/-female mice post-DOX relative to WT females, but not in p38 -/-or p38 -/- -/-male or female mice. The improved survival in DOX-treated p38 -/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38 -/-females. CONCLUSIONS: p38 plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38 targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. NEW AND NOTEWORTHY:This study for the first time identifies the roles of the alternative p38 and p38 MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38 systemic deletion did not affect DOX-cardiotoxicity, p38 systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38-/-females and autophagy was increased.

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Section: Introductionmentioning

confidence: 99%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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“…There are four p38MAPK isoforms, p38α, p38β, p38γ, and p38δ, encoded by different genes, which are activated in response to a range of cell stresses and in response to inflammatory cytokines (Cuenda & Sanz‐Ezquerro, ). Among them, p38α is crucial for the synthesis of pro‐inflammatory molecules and for the regulation of the immune response (Gaestel et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…Among them, p38α is crucial for the synthesis of pro‐inflammatory molecules and for the regulation of the immune response (Gaestel et al , ). Also, p38γ and p38δ (p38γ/p38δ) have recently been shown to play important roles in regulating cytokine production, T‐cell activation, insulin resistance, and in tumorigenesis associated with inflammation (Risco et al , ; Criado et al , ; Escós et al , ; Cuenda & Sanz‐Ezquerro, ). Although several studies have demonstrated that p38γ/p38δ are involved in inflammatory processes, the functional roles of these kinases in the innate immune responses have not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

et al. 2018

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Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.

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“…p38γ and p38δ are expressed in immune cells (Hale et al, 1999;Fearns et al, 2000;Cuenda and Rousseau, 2007;Cuenda and Sanz-Ezquerro, 2017). Using mice deficient in p38γ, p38δ, or both, we and other have showed that these kinases play a crucial role in inflammation and in the immune response (Ittner et al, 2012;Risco et al, 2012Risco et al, , 2018Cuenda and Sanz-Ezquerro, 2017;Alsina-Beauchamp et al, 2018).…”

Section: Introductionmentioning

confidence: 78%

“…The mammalian p38MAPK family is composed of four members (p38α, p38β, p38γ, and p38δ) encoded by distinct genes; they are broadly expressed and activated by a wide range of cellular stresses and in response to inflammatory cytokines. These kinases share highly similar protein sequences and all are activated by phosphorylation mediated primarily by MAPK kinases (MKK)3 and MKK6 (Remy et al, 2010); they nonetheless differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors, and represent related, but clearly distinct p38MAPK subgroups (p38α/p38β and p38γ/p38δ) (Cuenda et al, 1997;Cuenda and Rousseau, 2007;Cuenda and Sanz-Ezquerro, 2017). p38α, the most abundant and best-characterised p38MAPK isoform, is activated during both innate and adaptive immune responses, and is a key regulator of the immune response (Gaestel et al, 2009;Rincon and Davis, 2009); evidence is, however, emerging that implicates p38γ and p38δ in this process (Cuenda and Sanz-Ezquerro, 2017).…”

Section: Introductionmentioning

confidence: 99%

B Cell Development and T-Dependent Antibody Response Are Regulated by p38γ and p38δ

Barrio

Román‐García

Diaz-Mora

et al. 2020

Front. Cell Dev. Biol.

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p38MAP kinase (MAPK) signal transduction pathways are important regulators of inflammation and the immune response; their involvement in immune cell development and function is still largely unknown. Here we analysed the role of the p38 MAPK isoforms p38γ and p38δ in B cell differentiation in bone marrow (BM) and spleen, using mice lacking p38γ and p38δ, or conditional knockout mice that lack both p38γ and p38δ specifically in the B cell compartment. We found that the B cell differentiation programme in the BM was not affected in p38γ/δ-deficient mice. Moreover, these mice had reduced numbers of peripheral B cells as well as altered marginal zone B cell differentiation in the spleen. Expression of co-stimulatory proteins and activation markers in p38γ/δ-deficient B cells are diminished in response to B cell receptor (BCR) and CD40 stimulation; p38γ and p38δ were necessary for B cell proliferation induced by BCR and CD40 but not by TLR4 signaling. Furthermore, p38γ/δ-null mice produced significantly lower antibody responses to T-dependent antigens. Our results identify unreported functions for p38γ and p38δ in B cells and in the T-dependent humoral response; and show that the combined activity of these kinases is needed for peripheral B cell differentiation and function.

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p38γ and p38δ: From Spectators to Key Physiological Players

Cited by 73 publications

References 71 publications

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

B Cell Development and T-Dependent Antibody Response Are Regulated by p38γ and p38δ

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