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 6

C1q deficiency results in exaggerated smoke-induced emphysema.

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C1q deficiency results in exaggerated smoke-induced emphysema. WT mice a...
WT mice and C1qa–/– mice were exposed to cigarette smoke or air for 4 months. (A) Schematic diagram of experimental design. (B) Representative images of H&E-stained lung sections from air-exposed or smoke-exposed WT and C1qa–/– mice. Scale bar: 100 μm (25 μm in inset). (C) Bronchoalveolar lavage (BAL) fluid analyses from the same group of mice showing macrophages (Mac), neutrophils (Neu), eosinophil (Eos), and lymphocytes (Lym). n = 5 in WT Air; n = 4 in C1qa–/– Air; n = 4 in WT Smoke; n = 5 in C1qa–/– Smoke. Box, median and interquartile range; whiskers, min to max range. **P < 0.01, ***P < 0.001, as determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (D) Expression of Foxp3 mRNA in BAL cells was measured by quantitative reverse transcription PCR (qPCR). n = 5 in WT Air; n = 4 in C1qa–/– Air; n = 4 in WT Smoke; n = 5 in C1qa–/– Smoke. Box, median and interquartile range; whiskers, min to max range. Results are represented as mean ± SEM, from 2 independent experiments. *P < 0.05, as determined by the 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (E) Cumulative flow cytometry analysis showed the population of CD25+Foxp3+ CD4+ T cells in lungs of the same group of mice. n = 5 in WT Air; n = 4 in C1qa–/– Air; n = 4 in WT Smoke; n = 5 in C1qa–/– Smoke. Results are represented as mean ± SEM, from 2 independent experiments. *P < 0.05, was determined by the 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (F) Cumulative relative abundance of CD11b+CD11c+ lung APCs in the same experiment. n = 5 in WT Air; n = 4 in C1qa–/– Air; n = 4 in WT Smoke; n = 5 in C1qa–/– Smoke. Results are represented as mean ± SEM, from 2 independent experiments. *P < 0.05, was determined by 1-way ANOVA with Bonferroni’s correction for multiple comparisons. (G) Cumulative intracellular cytokine staining of IL-17A in CD3+/CD4+ T cell population. n = 5 in WT Air; n = 4 in C1qa–/– Air; n = 4 in WT Smoke; n = 5 in C1qa–/– Smoke. Results are represented as mean ± SEM, from 2 independent experiments. *P < 0.05, as determined by the 1-way ANOVA with Bonferroni’s correction for multiple comparisons.