Overexpression of Macrophage-Inducible C-Type Lectin Mincle Aggravates Proinflammatory Responses to Streptococcus pneumoniae with Fatal Outcome in Mice

Abstract

Macrophage-inducible C-type lectin (Mincle)-dependent sensing of pathogens triggers proinflammatory immune responses in professional phagocytes that contribute to protecting the host against pathogen invasion. In this study, we examined whether overexpression of Mincle that is designed to improve early pathogen sensing by professional phagocytes would improve lungprotective immunity against Streptococcus pneumoniae in mice. Proteomic profiling of alveolar macrophages of Mincle transgenic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1b cytokine release that was not observed in Glc-DAG-stimulated Mincle knockout or Nlrp3 knockout macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with S. pneumoniae, ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers increased Glc-DAG-dependent Nlrp3 inflammasome activation in professional phagocytes leading to fatal pneumococcal pneumonia in mice that is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of the Mincle receptor confers increased susceptibility rather than resistance to S. pneumoniae in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.

Effect of Mycolic Acids on Host Immunity and Lipid Metabolism

“…Researchers found that Mincle is an activating receptor that couples with the Fc receptor (FcRγ) and mediates immune response [ 22 ]. We hold the opinion that Mincle stimulated with the TDM revealed increased NLRP3 inflammasome activation and downstream IL-1β cytokine release [ 23 ]. The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3 with an additional adaptor molecule, an apoptosis-associated speck-like protein with a caspase recruitment domain encoded by Pycard (ASC), and caspase-1 [ 24 ].…”

“…Promotes neutrophil adhesion. [23,24,31] Trehalose dibehenate (TDB) Mincle 1. Production of inflammatory cytokines; 2.…”

Pleural Resident Macrophages and Pleural IRA B Cells Promote Efficient Immunity Against Pneumonia by Inducing Early Pleural Space Inflammation

“…The release of Damage-Associated Molecular Pattern (DAMPs) by necroptotic cells induces inflammation in the microenvironment ( 29 ), which are sensed by many receptors such as Mincle ( 35 ). Mincle is an inducible receptor expressed on myeloid cells ( 36 ) that plays an important role during bacterial pneumonia ( 21 , 37 ). At steady-state, we observed that Mincle was only expressed by pleural RM and its expression increased upon E.coli infection.…”

Mincle as a potential intervention target for the prevention of inflammation and fibrosis (Review)

“…Sharma et al ( 49 ) investigated the role of Mincle in pneumonic sepsis induced by Klebsiella pneumoniae ( K. pneumoniae ), which demonstrated that Mincle played a protective role by coordinating bacterial clearance mechanisms of neutrophils. A different study revealed that the Mincle-Glc-DAG axis is a lung protective immune factor in focal pneumonia induced by Streptococcus pneumoniae ( S. pneumoniae ) ( 50 ). In addition, it was revealed that leukocytes, especially neutrophils expressing Mincle, play a critical role in contributing to the regulation of protective immunity against focal pneumonia-causing S. pneumoniae ( 21 ).…”