Alveolar Macrophage Cathelicidin Deficiency in Severe Sarcoidosis

• Published in: Journal of innate immunity 2012-01, Vol.4 (5-6), p.569-578
• Main Authors: Barna, Barbara P., Culver, Daniel A., Kanchwala, Ali, Singh, Ravinder J., Huizar, Isham, Abraham, Susamma, Malur, Anagha, Marshall, Irene, Kavuru, Mani S., Thomassen, Mary Jane
• Format: Article
• Language: English
• Subjects: Adult; Alveoli; Antimicrobial agents; Antimicrobial Cationic Peptides - deficiency; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Biological and medical sciences; Bronchoalveolar Lavage Fluid - cytology; Bronchus; Calcitriol; cathelicidins; Cytokines; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; General aspects; Genetics of the immune response; Humans; Immune response; Immunobiology; Immunocytochemistry; Immunoregulation; Inflammation; Lung; Macrophages; Macrophages, Alveolar - metabolism; Male; Mathematics in biology. Statistical analysis. Models. Metrology. Data processing in biology (general aspects); Medical sciences; Middle Aged; Nuclear Receptor Coactivator 3 - genetics; Nuclear Receptor Coactivator 3 - metabolism; Polymerase chain reaction; Research Article; Sarcoidosis; Sarcoidosis, Pulmonary - metabolism; Sarcoidosis, Pulmonary - physiopathology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Serum levels; Severity of Illness Index; Steroid hormone receptors; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vitamin D - analogs & derivatives; Vitamin D - metabolism; Vitamin D receptors; Young Adult
• ISSN: 1662-811X; 1662-8128
• DOI: 10.1159/000339149

Background: Dysfunctional immune responses characterize sarcoidosis, but the status of cathelicidin, a potent immunoregulatory and antimicrobial molecule, has not been established in clinical disease activity. Methods: Alveolar macrophage cathelicidin expression was determined in biopsy-proven sarcoidosis patients classified clinically as ‘severe’ (requiring systemic treatment) or ‘non-severe’ (never requiring treatment). Bronchoalveolar lavage (BAL) cells from sarcoidosis patients and healthy controls were analyzed for mRNA expression of cathelicidin, vitamin D receptor (VDR) and the VDR coactivator steroid receptor coactivator-3 (SRC3) by quantitative PCR. Cathelicidin-derived peptide LL-37 was determined by immunocytochemistry. Serum calcidiol (25-hydroxyvitamin D2; vitD2) and calcitriol (1,25-dihydroxyvitamin D3; vitD3) were quantified. Results: The results indicated reduced BAL cell expression of cathelicidin and SRC3 in severe but not non-severe sarcoidosis compared to controls. Serum levels of biologically active vitD3 in both severe and non-severe patients were within the control range even though vitD2 levels in both groups were below the recommended level (30 ng/ml). Sarcoidosis and control alveolar macrophages were studied in vitro to determine cathelicidin responses to vitD3 and tumor necrosis factor-α (TNFα), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNFα, which also repressed SRC3. Conclusions: These findings suggest that TNFα-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. Deficiency of cathelicidin, a multifunctional regulator of immune cells and proinflammatory cytokines, may impede resolution of inflammation in the lungs of patients with severe sarcoidosis.