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 3

C1q enhances Tregs while it inhibits Th17 cell differentiation in vitro.

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C1q enhances Tregs while it inhibits Th17 cell differentiation in vitro....
Mouse CD4+ T cells were isolated from splenocytes by autoMACS. (A) Representative flow plot of CD4+ T cells isolated from the spleen and stimulated with anti-CD3/anti-CD28; cells were differentiated under Treg condition (TGF-β, anti–IL-4, anti–IFN-γ) with or without C1q for 3 days; CD4+ T cells in vehicle control condition were stimulated with anti-CD3/anti-CD28 but received PBS for 3 days. Tregs in culture were identified by flow cytometry using CD25 and Foxp3 markers. (B) Cumulative data shown in A were summarized (n = 3 for control and C1q; n = 6 for TGF-β and TGF-β + C1q). Results are represented as mean ± SEM, from 3 independent experiments. (C) Expression of Foxp3 mRNA in culture described in A was measured by qPCR (n = 5 in each group, normalized to 18S expression). Results are represented as mean ± SEM, from 3 independent experiments. (D) Representative CD4+ T cells differentiated under Th17 condition (e.g., IL-6, TGF-β, anti–IL-4, anti–IFN-γ) for 3 days. IL-17 production was measured using intracytoplasmic cytokine staining. (E) Cumulative data shown in (D) is summarized (n = 6 for control and C1q; n = 6 for TGF-β and TGF-β + C1q). (F) CD4+ T cells expressing RoRγt in culture described in D were measured by qPCR (n = 4 in each group, normalized to 18S expression). Results are represented as mean ± SEM, from 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001; P values were determined by 1-way ANOVA test with Bonferroni’s correction for multiple comparisons.