Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression

Abstract

Acute ethanol intoxication suppresses the host immune responses against Streptococcus pneumoniae. As interleukin 17 (IL-17) is a critical cytokine in host defense against extracellular pathogens, including S. pneumoniae, we hypothesized that ethanol impairs mucosal immunity against this pathogen by disrupting IL-17 production or IL-17 receptor (IL-17R) signaling. A chronic ethanol feeding model in simian immunodeficiency virus (SIV)-infected rhesus macaques and acute ethanol intoxication in a murine model were used. Transcriptome analysis of bronchial brushes in the nonhuman primate model showed downregulation of the expression of IL-17-regulated chemokines in ethanol-fed animals, a finding also replicated in the murine model. Surprisingly, recombinant CXCL1 and CXCL5 but not IL-17 or IL-23 plus IL-1␤ rescued bacterial burden in the ethanol group to control levels. Taken together, the results of this study suggest that ethanol impairs IL-17-mediated chemokine production in the lung. Thus, exogenous luminal restoration of IL-17-related chemokines, CXCL1 and CXCL5, improves host defenses against S. pneumoniae. Bacterial pneumonia is a complication of ethanol abuse, and this susceptibility was documented both in animal models and in human studies more than a century ago (1, 2). Excessive ethanol consumption remains a public health problem responsible for approximately 79,000 deaths in the United States each year and for an estimated economic cost of $223.5 billion in 2006 (3).Streptococcus pneumoniae is a Gram-positive bacterium and the leading etiology of community-acquired pneumonia, especially in older adults and alcoholic patients. Innate immune responses are important to control infections by S. pneumoniae, as evidenced by the roles of Toll-like receptors, MyD88, and IRAK4 in both humans and animal models (4, 5). More recently, evidence has emerged to support the fact that interleukin 17 (IL-17) plays a critical role in the regulation of S. pneumoniae colonization and infection. IL-17 and CD4 ϩ T cells, and specifically the Th17 subset, are important for clearance of nasopharyngeal colonization with S. pneumoniae (a prerequisite of pneumococcal pneumonia) during primary and secondary infection (6, 7).IL-17 is a cytokine produced by activated CD4 ϩ T cells and innate lymphocytes (␥␦ ϩ T cells, NK cells, and innate lymphoid cells) and drives inflammation and autoimmunity (8). In the lung, the airway epithelium plays an important role in orchestrating the production of C-X-C chemokines, and these cells express both IL-17RA and IL-17RC and can produce both C-X-C chemokines and granulocyte colony-stimulating factor (G-CSF) in response to IL-17, leading to neutrophil recruitment in vivo (9-11).As the lung epithelium is a major site of chemokine production during bacterial pneumonia (12), we examined the effect of ethanol on gene expression in the airway epithelium during experimental S. pneumoniae infection in a nonhuman primate model of ethanol consumption and pneumococcal infection (13,14). We analyzed bronchial b...

Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection

“…Chronic alcohol consumption has been correlated, as a comorbidity, to a wide range of health conditions, including alcoholic liver diseases, cirrhosis and cancers ( Szabo and Saha, 2015 ; Pritchard and Nagy, 2005 ; Szabo, 1999 ; Bautista, 1999 ; Luján et al, 2010 ). Moreover, alcohol abusers are prone to develop severe lung inflammatory and infectious diseases, including acute respiratory distress syndrome (ARDS) ( Liang et al, 2012 ), pneumonia caused by Streptococcus pneumoniae ( Trevejo-Nunez et al, 2015 ; Tsuchimoto et al, 2015 ; Boé et al, 2001 ), Klebsiella pneumoniae ( Yeligar et al, 2014 ; Ohama et al, 2015 ), Respiratory Syncytial Virus (RSV) infection ( Meyerholz et al, 2008 ) and aspergillosis ( Blum et al, 1978 ; Gustot et al, 2014 ). The mechanisms associated with this increased risk of disease and death are poorly understood, however studies have suggested that certain aspects of immune function may be altered by chronic ethanol intake ( D'Souza El-Guindy et al, 2007 ; Lippai et al, 2013 ; Yen et al, 2017 ; Zhang et al, 2015 ; Gurung et al, 2009 ).…”

Alcohol‐Induced Interleukin‐17 Expression Causes Murine Lung Fibroblast‐to‐Myofibroblast Transdifferentiation via Thy‐1 Down‐Regulation

“…Moreover, chronic alcohol ingestion increased lung‐specific Th17 development and IL‐17 expression in a postsurgical Klebsiella pneumoniae experimental model (Lanzke et al., ). Interestingly, in contrast to a daily chronic alcohol feeding model, there is a down‐regulation of IL‐17 expression 4 to 6 hours following alcohol ingestion in the lungs of mice in an alcohol binge model (Trevejo‐Nunez et al., ). These temporal changes in IL‐17 expression may be related to a sustained increase in the level of Th17‐polarizing cytokines such as IL‐6, TGF β 1, and IL‐23 that have been identified during chronic alcohol ingestion (Bechara et al., ; Rendon et al., ) that would not be present after a single alcohol binge.…”

Follistatin‐like protein 1 modulates IL‐17 signaling via IL‐17RC regulation in stromal cells

“…Additionally, multiple transcription factor‐binding sites have been identified within Il17rc exons, suggesting that several independent pathways may influence its expression. Furthermore, while IL‐17RC is highly expressed in bone, joint, prostate, liver and lung, IL‐17RC is selectively and minimally detected in the leukocyte compartment, suggesting that cell‐specific expression is tightly regulated 42 , 43 , 44 , 45 , 46 , 47 . Notably, several splice variants of Il17rc are expressed in a tissue‐specific manner, and factors influencing their regulation are unknown 47 , 48 .…”

“…Furthermore, while IL-17RC is highly expressed in bone, joint, prostate, liver and lung, IL-17RC is selectively and minimally detected in the leukocyte compartment, suggesting that cell-specific expression is tightly regulated. [42][43][44][45][46][47] Notably, several splice variants of Il17rc are expressed in a tissue-specific manner, and factors influencing their regulation are unknown. 47,48 Thus further study of the FSTL-1 regulation is likely to yield enhanced understanding of pathways influencing in IL17RC expression and possibly function.…”