Abstract
Among various innate immune receptor families, the role of C-type lectin receptors (CLRs) in lung protective immunity against Streptococcus pneumoniae (S. pneumoniae) is not fully defined. We here show that Mincle gene expression was induced in alveolar macrophages and neutrophils in bronchoalveolar lavage fluids of mice and patients with pneumococcal pneumonia. Moreover, S. pneumoniae directly triggered Mincle reporter cell activation in vitro via its glycolipid glucosyl-diacylglycerol (Glc-DAG), which was identified as the ligand recognized by Mincle. Purified Glc-DAG triggered Mincle reporter cell activation and stimulated inflammatory cytokine release by human alveolar macrophages and alveolar macrophages from WT but not Mincle KO mice. Mincle deficiency led to increased bacterial loads and decreased survival together with strongly dysregulated cytokine responses in mice challenged with focal pneumonia inducing S. pneumoniae, all of which was normalized in Mincle KO mice reconstituted with a WT hematopoietic system. In conclusion, the Mincle-Glc-DAG axis is a hitherto unrecognized element of lung protective immunity against focal pneumonia induced by S. pneumoniae.
Highlights
Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia (CAP)
Resident alveolar macrophages (AM) and neutrophils represent the first lines of host defense against lung-tropic bacterial pathogens, and have been characterized to express multiple pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors, as well as C-type lectin receptors (CLRs), all of which sense pathogen-associated molecular patterns (PAMPs) and/or danger-associated molecular patterns (DAMPs)
Mincle gene expression was significantly increased in alveolar macrophages and neutrophils of mice at 24 h post S. pneumoniae infection (Fig 1B)
Summary
Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia (CAP). Ligand binding to Mincle leads to phosphorylation of ITAM in the FcRγ chain and downstream recruitment of Syk kinase, followed by a heterotypic aggregation of Card with Bcl and Malt. Ligand binding to Mincle leads to phosphorylation of ITAM in the FcRγ chain and downstream recruitment of Syk kinase, followed by a heterotypic aggregation of Card with Bcl and Malt1 This signaling pathway results in an adaptive Th1 and Th17 cytokinedominated immune response and triggers production of cytokines such as TNF-α, IL-6, MIP2, IFN-γ and IL-17 [13,14,15]. Except for molecules having a similar structure with TDM, mannosyl fatty acids and β-gentiobiosyl glyceroglycolipids derived from Malassezia spp. are reported as Mincle ligands [19]. We recently demonstrated that Mincle is expressed on AM, newly recruited exudate macrophages and alveolar recruited neutrophils in response to Myocobacterium bovis (M. bovis) BCG infection, where it critically shaped the lung inflammatory response after mycobacterial challenge, and contributed to control of extrapulmonary M. bovis BCG infection in mice [22, 23]
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