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 8

Intranasal C1q decreases cigarette smoke–induced inflammatory cytokine and enhances Treg-related genes.

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Intranasal C1q decreases cigarette smoke–induced inflammatory cytokine a...
Expression of Il6 (A) and Il1beta (B) mRNA in BAL cells were measured by quantitative reverse transcription PCR (qPCR) in experimental conditions described in Figure 7 (normalized to 18S). n = 5 in each group. Box, median and interquartile range; whiskers, min to max range. **P < 0.01, as determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. Representative of 3 independent experiments. (C–E) Expression of Pparg (C) Foxp3 (D) and Il10 (E) mRNA in BAL cells was measured by quantitative reverse transcription PCR (qPCR, normalized to 18S). n = 5 in each group. Box, median and interquartile range; whiskers, min to max range. *P < 0.05, **P < 0.01, as determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. Representative of 3 independent experiments. (F) Cumulative data show relative abundance of CD25+Foxp3+ CD4+ T cells in the lungs of the same group of mice using flow cytometry. n = 5 in Air group; n = 4 in Smoke and Smoke + C1q group. Results are represented as mean ± SEM; representative of 3 independent experiments. *P < 0.05, as determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons.