Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages.
Eosinophils play a central role in the pathogenesis of tropical pulmonary eosinophilia, a rare, but fatal, manifestation of filariasis. However, no exhaustive study has been done to identify the genes and proteins of eosinophils involved in the pathogenesis of tropical pulmonary eosinophilia. In the present study, we established a mouse model of tropical pulmonary eosinophilia that mimicked filarial manifestations of human tropical pulmonary eosinophilia pathogenesis and used flow cytometry-assisted cell sorting and real-time RT-PCR to study the gene expression profile of flow-sorted, lung eosinophils and lung macrophages during tropical pulmonary eosinophilia pathogenesis. Our results show that tropical pulmonary eosinophilia mice exhibited increased levels of IL-4, IL-5, CCL5, and CCL11 in the bronchoalveolar lavage fluid and lung parenchyma along with elevated titers of IgE and IgG subtypes in the serum. Alveolar macrophages from tropical pulmonary eosinophilia mice displayed decreased phagocytosis, attenuated nitric oxide production, and reduced T-cell proliferation capacity, and FACS-sorted lung eosinophils from tropical pulmonary eosinophilia mice upregulated transcript levels of ficolin A and anti-apoptotic gene Bcl2,but proapoptotic genes Bim and Bax were downregulated. Similarly, flow-sorted lung macrophages upregulated transcript levels of TLR-2, TLR-6, arginase-1, Ym-1, and FIZZ-1 but downregulated nitric oxide synthase-2 levels, signifying their alternative activation. Taken together, we show that the pathogenesis of tropical pulmonary eosinophilia is marked by functional impairment of alveolar macrophages, alternative activation of lung macrophages, and upregulation of anti-apoptotic genes by eosinophils. These events combine together to cause severe lung inflammation and compromised lung immunity. Therapeutic interventions that can boost host immune response in the lungs might thus provide relief to patients with tropical pulmonary eosinophilia.
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India.
Pankaj
P
Sharma
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India.
Aditi
A
Sharma
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India.
Achchhe Lal
AL
Vishwakarma
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India.
Promod Kumar
PK
Agnihotri
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India.
Sharad
S
Sharma
*Parasitology Division, Sophisticated Analytical Instrument Facility, and Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India; and Academy of Scientific and Innovative Research, New Delhi, India mrigank_srivastava@cdri.res.in.
Mrigank
M
Srivastava
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D001119:Arginase / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D016207:Cytokines / Q000276:immunology; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D037102:Lectins / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000276:immunology; D001619:beta-N-Acetylhexosaminidases / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C413576:Retnla protein, mouse; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; C544448:Arg1 protein, mouse; D001119:Arginase
alternative activation; filariasis; flow cytometry; gene expression; proapoptotic genes