The Journal of immunology : official journal of the American Association of Immunologists
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Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. ⋯ There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.
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Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. ⋯ Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS.
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Multicenter Study Clinical Trial
A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid-Naive Mild Asthmatics.
A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. ⋯ This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.
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Peptidylarginine deiminase 4 (PAD4) catalyzes citrullination of histones, an important step for neutrophil extracellular trap (NET) formation. We aimed to determine the role of PAD4 during pneumonia. Markers of NET formation were measured in lavage fluid from airways of critically ill patients. ⋯ Moreover, Klebsiella and LPS could still induce NETosis in PAD4-/- neutrophils. Both groups showed largely similar bacterial growth, lung inflammation, and organ injury. In conclusion, these data argue against a major role for PAD4 in NET formation, host defense, or organ injury during pneumonia-derived sepsis.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. ⋯ We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.