Cigarette smoke–induced reduction of C1q promotes emphysema
Xiaoyi Yuan, Cheng-Yen Chang, Ran You, Ming Shan, Bon Hee Gu, Matthew C. Madison, Gretchen Diehl, Sarah Perusich, Li-Zhen Song, Lorraine Cornwell, Roger D. Rossen, Rick Wetsel, Rajapakshe Kimal, Cristian Coarfa, Holger K. Eltzschig, David B. Corry, Farrah Kheradmand
Xiaoyi Yuan, Cheng-Yen Chang, Ran You, Ming Shan, Bon Hee Gu, Matthew C. Madison, Gretchen Diehl, Sarah Perusich, Li-Zhen Song, Lorraine Cornwell, Roger D. Rossen, Rick Wetsel, Rajapakshe Kimal, Cristian Coarfa, Holger K. Eltzschig, David B. Corry, Farrah Kheradmand
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Research Article Immunology

Cigarette smoke–induced reduction of C1q promotes emphysema

Abstract

Alteration of innate immune cells in the lungs can promote loss of peripheral tolerance that leads to autoimmune responses in cigarette smokers. Development of autoimmunity in smokers with emphysema is also strongly linked to the expansion of autoreactive T helper (Th) cells expressing interferon γ (Th1), and interleukin 17A (Th17). However, the mechanisms responsible for enhanced self-recognition and reduced immune tolerance in smokers with emphysema remain less clear. Here we show that C1q, a component of the complement protein 1 complex (C1), is downregulated in lung CD1a+ antigen-presenting cells (APCs) isolated from emphysematous human and mouse lung APCs after chronic cigarette smoke exposure. C1q potentiated the function of APCs to differentiate CD4+ T cells to regulatory T cells (Tregs), while it inhibited Th17 cell induction and proliferation. Mice deficient in C1q that were exposed to chronic smoke exhibited exaggerated lung inflammation marked by increased Th17 cells, whereas reconstitution of C1q in the lungs enhanced Treg abundance, dampened smoke-induced lung inflammation, and prevented the development of emphysema. Our findings demonstrate that cigarette smoke–mediated loss of C1q could play a key role in reduced peripheral tolerance, which could be explored to treat emphysema.

Authors

Xiaoyi Yuan, Cheng-Yen Chang, Ran You, Ming Shan, Bon Hee Gu, Matthew C. Madison, Gretchen Diehl, Sarah Perusich, Li-Zhen Song, Lorraine Cornwell, Roger D. Rossen, Rick Wetsel, Rajapakshe Kimal, Cristian Coarfa, Holger K. Eltzschig, David B. Corry, Farrah Kheradmand

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Figure 2

Cigarette smoke inhibits C1q expression in APCs and increases Th17 cells.

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Cigarette smoke inhibits C1q expression in APCs and increases Th17 cells...
(A) Schematic diagram showing 4-month smoke, or air exposure using C57BL/6J (WT) mice. (B) Micro-CT analysis of lung volume from WT mice exposed to air or cigarette smoke for 4 months (n = 9 each). Box, median and interquartile range; whiskers, min to max range. (C) BAL cell differential shows increased macrophages and neutrophils in smoke-exposed mice; inset shows percentage composition of BAL cells in air- and smoke-exposed mice (n = 15 each). Box, median and interquartile range; whiskers, min to max range. (D) Expression of C1q mRNA in BAL cells isolated from mice exposed to 6 months of air or cigarette smoke was measured by qPCR and normalized to 18S expression. n = 24 in the air and n = 23 in the smoke group; ***P < 0.001, as determined by the Student’s t test. Box, median and interquartile range; whiskers, min to max range. (E) CD4+ splenic T cells isolated from naive WT mice were cocultured with APCs from WT or C1qa–/– mice at a 10:1 ratio (CD4+ T cells and APCs) for 3 days, and the population of Foxp3+ T cells were measured by flow cytometry. **P < 0.01 (n = 4). Results are represented as mean ± SEM, from 3 independent experiments. P values were determined by a 1-way ANOVA test with Bonferroni’s correction for multiple comparisons.