2017年伍安怡老師實驗室論文發表II
 

 2017年伍安怡老師實驗室論文發表  碩士生-- 張子軒

Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum

Tzu-Hsuan Chang1, Juin-Hua Huang1, Hsiu-Chao Lin1, Wen-Yu Chen1, Yu-Hsiang Lee1, Li-Chung Hsu2, Mihai G. Netea3, Jenny P.-Y. Ting4,5, Betty A. Wu-Hsieh1*

Abstract

Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with

pathogens and to process cytokines of the interleukin-1(IL-1) family into bioactive molecules. It has been established that

interleukin-1β (IL-1β) is important to host defense against Histoplasma capsulatum infection. However, the detailed

mechanism of how H. capsulatum induces inflammasome activation leading to IL-1β production has not been studied. Here,

we showed in dendritic cells (DCs) that H. capsulatum triggers caspase-1 activation and IL-1β production through NLRP3

inflammasome. By reciprocal blocking of Dectin-1 or Dectin-2 in single receptor-deficient DCs and cells from Clec4n-/-,

Clec7a-/-, and Clec7a-/-Clec4n-/- mice, we discovered that while Dectin-2 operates as a primary receptor, Dectin-1 serves as a

secondary one for NLRP3 inflammasome. In addition, both receptors trigger Syk-JNK signal pathway to activate signal 1 (pro-

IL-1β synthesis) and signal 2 (activation of caspase-1). Results of pulmonary infection with H. capsulatum showed that

CD103+ DCs are one of the major producers of IL-1β and Dectin-2 and Dectin-1 double deficiency abolishes their IL-1β

response to the fungus. While K+ efflux and cathepsin B (but not ROS) function as signal 2, viable but not heat-killed H.

capsulatum triggers profound lysosomal rupture leading to cathepsin B release. Interestingly, cathepsin B release is regulated

by ERK/JNK downstream of Dectin-2 and Dectin-1. Our study demonstrates for the first time the unique roles of Dectin-2 and

Dectin-1 in triggering Syk-JNK to activate signal 1 and 2 for H. capsulatum-induced NLRP3 inflammasome activation.

PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1006485 July 3, 2017