TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA.

p38γ and p38δ (p38γ/p38δ) regulate inflammation, in part by controlling tumor progression locus 2 (TPL2) expression in myeloid cells. Here, we demonstrate that TPL2 protein levels are dramatically reduced in p38γ/p38δ-deficient (p38γ/δ-/-) cells and tissues without affecting TPL2 messenger ribonucleic acid (mRNA) expression. We show that p38γ/p38δ posttranscriptionally regulates the TPL2 amount at two different levels. p38γ/p38δ interacts with the TPL2/A20 Binding Inhibitor of NF-κB2 (ABIN2)/Nuclear Factor κB1p105 (NF-κB1p105) complex, increasing TPL2 protein stability. Additionally, p38γ/p38δ regulates TPL2 mRNA translation by modulating the repressor function of TPL2 3' Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by TPL2 3'UTR and severely decreases TPL2 protein levels. p38δ binds to ACO1, and p38δ expression in p38γ/δ-/- cells fully restores TPL2 protein to wild-type levels by reducing the translational repression of TPL2 mRNA. This study reveals a unique mechanism of posttranscriptional regulation of TPL2 expression, which given its central role in innate immune response, likely has great relevance in physiopathology.

Are patients with bipolar disorder and comorbid attention-deficit hyperactivity disorder more neurocognitively impaired?

OBJECTIVE: Research on neurocognitive impairment in adult patients with comorbid bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) is very scarce. This study assessed the neurocognitive profile of a comorbid group (BD+ADHD) compared with that of pure BD (pBD) group, pure ADHD (pADHD) group and healthy controls (HCs). METHODS: This was a three-site study comprising 229 subjects: 70 patients with pBD, 23 with BD+ADHD, 50 with pADHD, and 86 HCs. All patients with BD had been euthymic for at least 6 months. Neuropsychological performance was assessed using a comprehensive neurocognitive battery. RESULTS: Our results showed that all the clinical groups had poorer performance than the HCs in all the neurocognitive domains except for executive functions. No significant differences were observed between the pBD and BD+ADHD groups in any of the cognitive domains, with these two groups showing greater impairment than the pADHD group in executive functions and visual memory. CONCLUSIONS: Our results, although preliminary, suggest that the BD+ADHD group showed the same neurocognitive profile as pBD patients, most likely reflecting the same neurobiological basis. On the other hand, the pADHD group showed a more selective moderate impairment in attention.

p38δ controls Mitogen- and Stress-activated Kinase-1 (MSK1) function in response to toll-like receptor activation in macrophages.

Mitogen- and Stress-activated Kinase (MSK) 1 is a nuclear protein, activated by p38α Mitogen-Activated Kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2), that modulate the production of certain cytokines in macrophages. Using knockout cells and specific kinase inhibitors, we show that, besides p38α and ERK1/2, another p38MAPK, p38δ, mediates MSK phosphorylation and activation, in LPS-stimulated macrophages. Additionally, recombinant MSK1 was phosphorylated and activated by recombinant p38δ, to the same extent than by p38α, in in vitro experiments. Moreover, the phosphorylation of the transcription factors CREB and ATF1, that are MSK physiological substrates, and the expression of the CREB-dependent gene encoding DUSP1, were impaired in p38δ-deficient macrophages. Also, the transcription of IL-1Ra mRNA, that is MSK-dependent, was reduced. Our results indicate that MSK activation can be one possible mechanism by which p38δ regulates the production of a variety of inflammatory molecules involved in immune innate response.

Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress.

p38 kinases are key elements of the cellular stress response in animals. They mediate the cell response to a multitude of stress stimuli, from osmotic shock to inflammation and oncogenes. However, it is unknown how such diversity of function in stress evolved in this kinase subfamily. Here, we show that the p38 kinase was already present in a common ancestor of animals and fungi. Later, in animals, it diversified into three JNK kinases and four p38 kinases. Moreover, we identified a fifth p38 paralog in fishes and amphibians. Our analysis shows that each p38 paralog has specific amino acid substitutions around the hinge point, a region between the N-terminal and C-terminal protein domains. We showed that this region can be used to distinguish between individual paralogs and predict their specificity. Finally, we showed that the response to hyperosmotic stress in Capsaspora owczarzaki, a close unicellular relative of animals, follows a phosphorylation-dephosphorylation pattern typical of p38 kinases. At the same time, Capsaspora's cells upregulate the expression of GPD1 protein resembling an osmotic stress response in yeasts. Overall, our results show that the ancestral p38 stress pathway originated in the root of opisthokonts, most likely as a cell's reaction to salinity change in the environment. In animals, the pathway became more complex and incorporated more stimuli and downstream targets due to the p38 sequence evolution in the docking and substrate binding sites around the hinge region. This study improves our understanding of p38 evolution and opens new perspectives for p38 research.

p38γ and p38δ modulate innate immune response by regulating MEF2D activation.

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using Mapk12/Mapk13-deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here, we generated a Mapk12D171A/D171A/Mapk13-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to lipopolysaccharide (LPS)-induced septic shock and Candida albicans infection than wild-type (WT) mice. Gene expression analyses in LPS-activated wild-type and p38γ/δKIKO macrophages revealed that p38γ/p38δ-regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of Nos2 and Il1b mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.

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

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.

High BDNF serum levels are associated to good cognitive functioning in bipolar disorder.

BACKGROUND: Neurotrophins such as brain-derived neurotrophic factor (BDNF), inflammation and oxidative damage may contribute to the pathophysiology of bipolar disorder (BD) in terms of illness activity. To date, there is a lack of studies linking the cognitive impairment observed in BD with these neurobiological mechanisms. This study aimed to investigate the role of these neurobiological factors in clinical and cognitive outcomes in a sample of bipolar individuals. METHODS: We measured serum BDNF, cytokines and oxidative stress markers in a sample of 133 individuals: 52 euthymic bipolar patients, 32 manic patients and 49 healthy controls. They were all assessed with a comprehensive cognitive battery. Sociodemographic and clinical data were collected. Multiple linear regression models were built to study associations of neurotrophins and inflammatory and oxidative measures with cognitive functioning. RESULTS: BDNF levels were decreased in euthymic (p = 0.039) and manic (p < 0.001) individuals. Conversely, inflammatory (interleukin 6 (IL-6)) (p = 0.019) and oxidative stress (p = 0.003) measures were increased in bipolar individuals compared to controls. BDNF levels were associated with executive functioning (ß = 0.01, p = 0.02) and verbal memory (ß = 0.013, p = 0.005), together with other demographic variables. In particular, verbal memory was also associated with obesity (ß=-0.04, p = 0.005). Neither inflammatory markers, oxidative stress markers nor other relevant clinical variables showed any association with cognitive outcome. CONCLUSIONS: Of all the peripheral neurobiological factors analysed, BDNF was the only one significantly associated with cognitive dysfunction in bipolar disorder individuals. This study emphasizes the role of BDNF not only across mood phases but also in cognitive functioning.

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

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.

The Impact of Obesity on Cognitive Functioning in Euthymic Bipolar Patients: A Cross-Sectional and Longitudinal Study.

OBJECTIVE: To determine the influence of body mass index (BMI) on cognition in euthymic bipolar patients and healthy matched controls in a post hoc study of 2 cross-sectional and longitudinal exploratory studies. METHOD: A total sample of 121 individuals was examined, which included 52 euthymic bipolar disorder I or II patients (DSM-IV-TR criteria) and 69 healthy controls matched by age and gender, categorized in 2 subgroups in terms of body mass index (BMI-factor): normal weight (BMI: 18.5-24.9 kg/m²) versus overweight-obesity (overweight, BMI: 25.0-29.9 kg/m²; and obese, BMI ≥ 30 kg/m²). Demographic, clinical, cognitive, and psychosocial functioning data were collected from 2003 until 2011. Cognitive domains studied were executive function, attention, processing speed, verbal memory, and visual memory. Fifty-four subjects (28 bipolar and 26 healthy controls) were reevaluated after 6 years of follow-up. RESULTS: Obesity and bipolar disorder showed a significant effect on cognition in cross-sectional and long-term MANOVA analyses (F7,111 = 2.54, P = .018 and F19,23 = 2.25, P = .033, respectively). In the cross-sectional linear regression model, global cognitive functioning was predicted by the interaction of BMI-factor by group (ß = -0.44, SE = 0.14, P = .002), current age (ß = -0.44, P < .0001), and premorbid IQ (ß = 0.28, P = .0002), which explained 56% of variance (F5,115 = 29.6, P < .0001). Change in cognitive functioning over time was predicted by the interaction of BMI-factor by group (ß = -0.8, SE = 0.33, P = .022) and cognition at baseline (ß = -0.46, SE = 0.15, P = .004), which explained 27.65% of variance (F6,40 = 2.548, P = .0349). Generalized estimating equations analysis showed that interaction of group by BMI (Wald χ²1 = 5.37, P = .02), age (Wald χ²1 = 22.08, P < .0001), and premorbid IQ (Wald χ²1 = 25.65, P < .0001) were the significant predictors. CONCLUSIONS: Obesity was significantly associated with cognitive impairment in euthymic bipolar patients, and it also appeared to affect cognition in the long term.

The influence of cognitive reserve on psychosocial and neuropsychological functioning in bipolar disorder.

Cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain pathology in order to minimize symptomatology. CR was initially investigated in dementia and acute brain damage, but it is being applied to other neuropsychiatric conditions. The present study aims at examining the fit of this concept to a sample of euthymic bipolar patients compared with healthy controls in order to investigate the role of CR in predicting psychosocial and cognitive outcome in bipolar disorder (BD). The sample included 101 subjects: 52 patients meeting DSM-IV-TR criteria for BD type I or II and 49 healthy controls (HC) matched for age and gender. They were all assessed with a cognitive battery tapping into executive and memory functioning. CR was obtained using three different proxies: education-occupation, leisure activities and premorbid IQ. Psychosocial functioning was evaluated by means of the Functioning Assessment Short Test (FAST). MANCOVAs were performed to determine differences in cognitive and functioning variables. Linear regression analyses were carried out to predict neuropsychological and psychosocial outcomes. Euthymic bipolar patients showed worse neuropsychological performance and psychosocial functioning than HC. The linear regression models revealed that CR was significantly predictive of FAST score (ß = -0.47, p < 0.0001), Executive Index (ß = 0.62, p < 0.0001) and Visual Memory Index (ß = 0.44, p = 0.0004), indicating that CR is a significant predictor of cognitive and psychosocial functioning in euthymic bipolar outpatients. Therefore, CR may contribute to functional outcome in BD and may be applied in research and clinical interventions to prevent cognitive and functional impairment.