Lysosomal phospholipase A₂: A novel player in host immunity to Mycobacterium tuberculosis

Abstract

Phospholipases catalyze the cleavage of membrane phospholipids into smaller bioactive molecules. The lysosomal phospholipase A 2 (LPLA 2 ) is specifically expressed in macrophages. LPLA 2 gene deletion in mice causes lysosomal phospholipid accumulation in tissue macrophages leading to phospholipidosis. This phenotype becomes most prominent in alveolar macrophages where LPLA 2 contributes to surfactant phospholipid degradation. High expression of LPLA 2 in alveolar macrophages prompted us to investigate its role in host immunity against the respiratory pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis. Here we report that adaptive immune responses to M. tuberculosis were impaired in LPLA 2 deficient mice. Upon aerosol infection with M. tuberculosis, LPLA 2 deficient mice showed enhanced mycobacterial counts but less lung immunopathology and pulmonary inflammatory responses. Compromised T-cell priming in the lymph nodes was associated with impaired pulmonary T-cell recruitment and activation. Together with reduced Th1 type cytokine production, these results indicate that LPLA 2 is indispensable for the induction of adaptive T-cell immunity to M. tuberculosis. Taken together, we identified an unexpected and novel function of a lysosomal phospholipid-degrading enzyme.Keywords: Immunity r Macrophages r Phospholipase r T cells r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPhospholipases form a ubiquitous class of enzymes that cleave membrane phospholipids into smaller bioactive molecules [1]. Enzymes of the phospholipase A 2 (PLA 2 ) family play multiCorrespondence: Prof. Ulrich E. Schaible e-mail: uschaible@fz-borstel.de ple roles in lung infection and inflammation [2]. Apart from being involved in the generation of bioactive lipids such as eicosanoids, which are involved in inflammation by regulating cytokine and chemokine responses, direct bactericidal activity due to hydrolysis of bacterial-membrane phospholipids has also been shown for secretory PLA 2 (sPLA 2 ) [2,3]. Despite the essential function of lysosomes for membrane degradation, which is a primary function of phagocytes, only a few responsible enzymes were identified so far. The lysosomal phospholipase A 2 (LPLA 2 ), C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2394-2404 Immunity to infection 2395 newly designated group XV PLA A 2 , is specifically expressed in macrophages with predominance in alveolar macrophages where it is of specific relevance for surfactant phospholipid degradation [4]. LPLA 2 is a broad specificity PLA 2 that is characterized by the presence of both PLA 2 and transacylase activity [5]. Among the main substrates of the LPLA 2 are phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which account for 84 and 2% of the surfactant lipid in mice, respectively [4]. LPLA 2 knockout mice develop a lysosomal storage disease, that is, phospholipidosis, which becomes obvio...

Macrophage–Bacteria Interactions—A Lipid-Centric Relationship

“…While bacterial phospholipases can be detrimental to the host, conversely, host phospholipase activities can antagonize the survival of intracellular pathogens. In the context of mycobacterial infections, host phospholipase D and lysosomal phospholipase A2 have been implicated in the cells’ ability to control intracellular mycobacterial growth ( 94 , 95 ). It should be noted that these studies were focused on the enzymes, and the exact lipid mediators remain to be identified.…”

Lipoquality control by phospholipase A₂ enzymes

“…Genetic deletion of LPLA 2 results in unusual accumulation of non-degraded lung surfactant phospholipids in lysosomes of alveolar macrophages, leading to phospholipidosis, 80 ) perturbed presentation of endogenous lysophospholipid antigens to CD1d by invariant natural killer T (iNKT) cells, 81 ) and impairment of adaptive T cell immunity against mycobacterium. 82 )…”

Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase

“…LPLA2 is ubiquitously expressed but is most abundant in terminally differentiated alveolar macrophages 3 and is important for lung surfactant metabolism 4 and maturation of invariant natural killer T cells 5 . Inhibition of LPLA2 might be responsible for cellular toxicities caused by the administration of cationic amphiphilic drugs such as amiodarone 6 , and recent studies on LPLA2 knockout mice have linked LPLA2 to lupus erythematosus 1 and the innate immune response to infection by mycobacteria 7 . LCAT, 50% identical in amino acid sequence to LPLA2, associates with high and low density lipoprotein (HDL and LDL) particles in plasma and catalyzes an essential step in reverse cholesterol transport from peripheral tissues to the liver 8 .…”