Abstract
LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that Histoplasma capsulatum is taken into LAPosome upon phagocytosis by macrophages. Interaction of H. capsulatum with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/β or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to H. capsulatum. Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from Nlrx1−/− mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to H. capsulatum. Furthermore, inhibiting ROS production in Nlrx1−/− macrophages almost completely abolishes H. capsulatum-induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by H. capsulatum for macrophage cytokine response.
Highlights
Histoplasma capsulatum is a pathogenic dimorphic fungus that can cause flu-like respiratory illness in humans
We discovered that signaling downstream of Dectin-1 facilitated NADPH oxidasederived reactive oxygen species (ROS) response which was required for LC3-associated phagocytosis (LAP) induction by H. capsulatum
LC3-associated phagocytosis (LAP) bridging pattern-recognition receptors (PRRs) signaling to autophagic machinery has been described as an innate defense mechanism against fungal pathogens [20,21,22,23,24]
Summary
Histoplasma capsulatum is a pathogenic dimorphic fungus that can cause flu-like respiratory illness in humans. Recognition of H. capsulatum by macrophage through CR3 and Dectin-1 triggers TNF and IL-6 production that orchestrates adaptive immune response against the infection [7]. Mice defective in both CR3 and Dectin-1 are impaired in TNF and IL-6 production, which results in reduced Th1 and Th17 responses and heightened susceptibility to histoplasmosis [7]. Given the multiple roles of macrophage in host defense against H. capsulatum, a better understanding of its interaction with the fungus is crucial for the development of new therapeutic strategies against histoplasmosis
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