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 7

Intranasal C1q attenuates cigarette smoke–induced emphysema.

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Intranasal C1q attenuates cigarette smoke–induced emphysema. WT mice wer...
WT mice were exposed to cigarette smoke or air for 6 months. Intranasal (i.n.) C1q was given to smoke-exposed mice (20 μg, twice per week) for a total of 6 weeks before termination of the experiment at 6 months. (A) Schematic representation of experimental design. (B) Micro-CT quantification of lung volume and (C) representative images of H&E-stained lung sections from air-exposed, smoke-exposed, and smoke-exposed mice treated with C1q. Scale bar: 100 μm (25 μm in inset). n = 4 in each group. Results are represented as mean ± SEM, from 3 independent experiments. **P < 0.01, was determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (D) Mean linear intercept using unbiased morphometry in the indicated groups of mice described in (A). n = 10 in each group. Results are represented as mean ± SEM, from 3 independent experiments. ***P < 0.001, was determined by the 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (E) Bronchoalveolar lavage (BAL) fluid analyses from the same group of mice showing macrophages (Mac), neutrophils (Neu), eosinophil (Eos), and lymphocytes (Lym). n = 4 in each group. Box, median and interquartile range; whiskers, min to max range. *P < 0.05, was determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. Representative of 3 independent experiments. (F) Cumulative intracellular cytokine staining of IL-17A in CD3+/CD4+ T cells. n = 4 in each group. Results are presented as mean ± SEM; representative of 3 independent experiments. *P < 0.05, was determined by the 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (G) Cumulative relative abundance of CD11b+CD11c+ lung APCs in the same experiment. n = 4 in each group. Results are represented as mean ± SEM, from 3 independent experiments.