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 5

Increased T cell activation in C1qa–/– mice.

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Increased T cell activation in C1qa–/– mice. Total splenocytes were isol...
Total splenocytes were isolated from 12-month-old WT or C1qa–/– mice. Representative histograms and summarized mean fluorescence intensity of CD62L on CD4+ (A and B) and CD8+ (C and D) T cells as measured by flow cytometry. n = 4 in each group. Results are represented as mean ± SEM, from 2 independent experiments. ***P < 0.001 was determined by Student’s t test. (E) Relative abundance of CD25+Foxp3+ CD4+ T cell population in the spleen was measured by flow cytometry. n = 6 in WT and n = 5 in C1qa–/– group. Results are represented as mean ± SEM, from 2 independent experiments. ***P < 0.001 was determined by Student’s t test. Representative histogram and summarized the mean fluorescent intensity of CD62L (F and G) and ICOS (H and I) on CD4+ Foxp3+ T cells in the spleen. n = 4 in each group. Results are represented as mean ± SEM, from 2 independent experiments. **P < 0.01 was determined by Student’s t test.