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.

Epithelial-Immune Cell Interactions for Drug Discovery in Chronic Obstructive Pulmonary Disease.

New studies of chronic obstructive pulmonary disease (COPD) are revealing the key role of airway epithelial cells and innate immune cells in the initiation, exacerbation, and progression of airway disease. An emerging scheme focuses on expansion of airway progenitor epithelial cells that feed forward for a type 2 immune response and consequent IL-13-driven mucus production that is linked to the morbidity and mortality of COPD. Analysis of human airway progenitor epithelial cells and airway tissue shows that IL-13 signaling to MUC5AC mucin gene expression relies on specific activation of mitogen-activated protein kinase 13, providing a druggable target for attenuating mucus production in the setting of viral infection and other inhaled stimuli of airway inflammation. Moreover, structure-based drug design is delivering highly potent, selective, and nontoxic small-molecule kinase inhibitors of mitogen-activated protein kinase 13 that offer a therapeutic strategy to downregulate excess mucus production to a physiological level and thereby achieve a precision medicine solution to the major health care problem of COPD and related airway diseases.

p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.

p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion.

Cholangiocarcinoma (CC) and hepatocellularcarcinoma (HCC) are two main forms of liver malignancies, which exhibit differences in drug response and prognosis. Immunohistotochemical staining for cytokeratin markers has been used to some success in the differential diagnosis of CC from HCC. However, there remains a need for additional markers for increased sensitivity and specificity of diagnosis. In this study, we have identified a p38 MAP kinase, p38delta (also known as MAPK13 or SAPK4) as a protein that is upregulated in CC relative to HCC and to normal biliary tract tissues. We performed microarray gene expression profiling on 17 cases of CC, 12 cases of adjacent normal liver tissue, and three case of normal bile duct tissue. p38delta was upregulated in 16 out of 17 cases of CC relative to normal tissue. We subsequently performed immunohistochemical staining of p38delta in 54 cases of CC and 54 cases of HCC. p38delta staining distinguished CC from HCC with a sensitivity of 92.6% and a specificity of 90.7%. To explore the possible functional significance of p38delta expression in CC, we examined the effects of overexpression and knockdown of p38delta expression in human CC cell lines. Our results indicate that p38delta is important for motility and invasion of CC cells, suggesting that p38delta may play an important role in CC metastasis. In summary, p38delta may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease.