CX3CR1+ lung mononuclear phagocytes spatially confined to the interstitium produce TNF-α and IL-6 and promote cigarette smoke-induced emphysema

Zeyu Xiong, Adriana S. Leme, Prabir Ray, Steven D. Shapiro, Janet S. Lee

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-α and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1GFP/GFP and cx3cr1GFP/+ mice failed to show recruitment of CX3CR1+ cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1 +CD11b+ mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1-CX3CR1 pathway amplified the percentage of CX3CR1+CD11b+ mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-a and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1+ "tissue resident" mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.

Original languageEnglish
Pages (from-to)3206-3214
Number of pages9
JournalJournal of Immunology
Volume186
Issue number5
DOIs
StatePublished - Mar 1 2011

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