Cigarette smoke–induced reduction of C1q promotes emphysema
Xiaoyi Yuan, … , David B. Corry, Farrah Kheradmand
Xiaoyi Yuan, … , David B. Corry, Farrah Kheradmand
Published May 21, 2019
Citation Information: JCI Insight. 2019;4(13):e124317. https://doi.org/10.1172/jci.insight.124317.
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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 1

mRNA expression and protein concentration of C1q are reduced in human emphysema.

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mRNA expression and protein concentration of C1q are reduced in human em...
(A) Heatmap using microarray of C1q expression in lung CD1a+ cells isolated from control and emphysema patients (GSE26296). (B) Expression of C1QA mRNA in CD1a+ APCs isolated from total lung cells was measured by qPCR (normalized to 18S expression). Ctrl, control (smokers without emphysema); N = 26. (C) The same data were used to separate subjects based on current (active) vs. former (>1 year inactive) smoking history. **P < 0.01. (D) Linear regression was used to find the correlation between C1QA mRNA in CD1a+ APCs and airway obstruction as measured by lung function (% forced expiratory volume in 1 second; FEV1). (E) Plasma samples from control (n = 48) and emphysema patients (n = 60) were used to measure C1q concentration using ELISA. Box, median and interquartile range; whiskers, min to max range. ***P < 0.001. (F) Human CD1a+ lung cells isolated by autoMACS were cultured in complete medium (RPMI-1640 with 10% FBS and Pen-Strep) at a concentration of 1 × 106/mL and treated with increasing concentration of purified human IL-1β (100 pg/mL, 1 ng/mL) for 48 hours or with medium alone as the vehicle. The expression level of C1QA was measured by quantitative reverse transcription PCR (qPCR). (Normalized to 18S expression). n = 3; *P < 0.05. Results are represented as mean ± SEM, from 3 independent experiments. (G) Knockdown of C1QA expression in human cDCs was achieved by transfection of C1QA-specific siRNA. Scrambled siRNA was transfected as a control. The expression of C1QA mRNA was measured by qPCR (Normalized to 18S expression). ***P < 0.001. (H and I) CD4+ T cells isolated from PBMCs were cocultured with allogeneic APCs shown in 10:1 ratio (CD4+ T cells and APCs) for 3 days, and CD25+Foxp3+ (H) and CD25+Foxp3– (I) T cell population were measured using flow cytometry. ***P < 0.001. (J) The concentration of IL-17A in the supernatant from cell cultures in (I) was measured by multiplex assay. ***P < 0.001. P values were determined by the Mann-Whitney nonparametric test.