Aspergillus fumigatus-induced Interleukin-8 Synthesis by Respiratory Epithelial Cells Is Controlled by the Phosphatidylinositol 3-Kinase, p38 MAPK, and ERK1/2 Pathways and Not by the Toll-like Receptor-MyD88 Pathway

Abstract

Previous studies have established that phagocytes are key cells of the pulmonary innate immune defense against A. fumigatus, an opportunistic fungus responsible of invasive pulmonary aspergillosis. Macrophages detect A. fumigatus via Toll-like receptors 2 and 4 (TLR2 and -4) and respond by the MyD88-NF-B-dependent synthesis of inflammatory mediators. In the present study, we demonstrate that respiratory epithelial cells also sense A. fumigatus and participate in the host defense. Thus, the interaction of respiratory epithelial cells with germinating but not resting conidia of A. fumigatus results in interleukin (IL)-8 synthesis that is controlled by phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2. Using MyD88-dominant negative transfected cells, we also show that IL-8 production is not dependent on the TLR-MyD88 pathway, although the MyD88 pathway is activated by A. fumigatus and leads to NF-B activation. Thus, our results provide evidence for the existence of two independent signaling pathways activated in respiratory epithelial cells by A. fumigatus, one that is MyD88-dependent and another that is My88-independent and involved in IL-8 synthesis.Aspergillus fumigatus is an opportunistic fungus responsible for invasive pulmonary aspergillosis (IPA), 2 a lifethreatening disease that usually only occurs in immunocompromised patients as inhalation of spores by those hosts results in fungal growth inside the lung and hematogenous dissemination (1, 2).The mechanisms of host resistance to IPA are not completely understood. It is generally accepted that macrophages and neutrophils represent the first two lines of innate host defense against A. fumigatus (3, 4). Specifically, alveolar macrophages phagocyte and kill conidia, whereas neutrophils lyse hyphae of germinated spores (5). However, it is now recognized that epithelial cells also play an important role in the innate defense (6 -8). Rather than just representing a physical barrier to prevent pathogen gaining unwanted access to essential organs, the epithelial layer provides a surface where the host can interact with pathogens. The airway epithelium senses micro-organisms and responds accordingly by increasing its defense. This response consists of the synthesis and release of antimicrobial peptides, cytokines, and chemokines. As do macrophages and neutrophils, epithelial cells can also sense microbial products through pattern recognition receptors that bind conserved molecular patterns expressed by micro-organisms.Toll-like receptors (TLRs) have been identified as a major class of pattern recognition receptors (9 -11). Recognition of pathogen-associated molecular patterns by TLRs triggers a cascade of cellular signals that culminates in the activation of NF-B, which leads to inflammatory gene expression and ultimately to the clearance of the infectious agents (11-14). There is accumulating evidence, based on in vitro and in vivo studies, that supports a role for TLRs in A. fumigatus sensing. Findings from various studies demonstrated that A. fumigatus recognit...

Transcriptome Profiling and Functional Analyses of the Zebrafish Embryonic Innate Immune Response to Salmonella Infection

“…Furthermore, we have identified mmp9 and irak3 as novel MyD88-dependent immune response genes. MyD88-dependent as well as MyD88-independent induction of IL-8 has been observed in mammalian systems (57,58). However, regarding the Myd88-independent il8 induction that we observed in zebrafish embryos, note that the orthology of this gene with mammalian IL-8 is ambiguous and that zebrafish express other closely related putative IL-8 homologs.…”

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

“…In this regard, despite the fact that airways ECs phagocytose Aspergillus conidia, 16,17 the ability of conidia to survive in ECs 17 was taken to indicate airways ECs as a possible fungus reservoir. More recently, ECs were found to respond to Aspergillus conidia via MyD88-dependent and -independent pathways 18 and by upregulating antimicrobial peptides 43,44 endowed with antifungal activity. 45 Thus, the production of IL-17A, known to induce antimicrobial peptides, 46 is of particular interest and worth of further investigation.…”

“…16,17 However, respiratory ECs also sense germinating conidia through MyD88-dependent and -independent pathways. 18 Of interest, IDO overexpression from the airway ECs was found to restrain CD4 1 T-cell activation to the fungus, an activity that was nevertheless dispensable in the presence of IDO-expressing DCs. 19 In the present study, we assess the contribution of ECs to protective immunity to Aspergillus and the possible mechanisms underlying this activity in experimental models of pulmonary aspergillosis.…”

Immunity status of invasive pulmonary aspergillosis patients with structural lung diseases in Chinese adults

“…In COPD, although there is increased recruitment and activation of eosinophils, pulmonary alveolar macrophages (PAMs), and lymphocytes within the lungs, their immune functions of phagocytosis and chemotaxis are qualitatively altered (24,25). Evidence now shows that COPD progresses to systemic autoimmunity, possibly through spillover from the primary pulmonary inflammatory input (26)(27)(28). The recognition of pathogen-associated molecular patterns by host cell pattern recognition receptors (PRRs) is the first step of phagocytosis, leading to a pro-inflammatory response characterized by the production of cytokines and chemokines.…”