Diverse and Potent Chemokine Production by Lung CD11bhigh Dendritic Cells in Homeostasis and in Allergic Lung Inflammation

Abstract

Lung CD11chigh dendritic cells (DC) are comprised of two major phenotypically distinct populations, the CD11bhigh DC and the integrin αEβ7+ DC (CD103+ DC). To examine whether they are functionally distinguishable, global microarray studies and real-time PCR analysis were performed. Significant differences between the two major CD11chigh DC types in chemokine mRNA expression were found. CD11bhigh DC is a major secretory cell type and highly expressed at least 16 chemokine mRNA in the homeostatic state, whereas CD103+ DC highly expressed only 6. Intracellular chemokine staining of CD11chigh lung cells including macrophages, and ELISA determination of sort-purified CD11chigh cell culture supernatants, further showed that CD11bhigh DC produced the highest levels of 9 of 14 and 5 of 7 chemokines studied, respectively. Upon LPS stimulation in vitro and in vivo, CD11bhigh DC remained the highest producer of 7 of 10 of the most highly produced chemokines. Induction of airway hyperreactivity and lung inflammation increased lung CD11bhigh DC numbers markedly, and they produced comparable or higher amounts of 11 of 12 major chemokines when compared with macrophages. Although not a major producer, CD103+ DC produced the highest amounts of the Th2-stimulating chemokines CCL17/thymus and activation-related chemokine and CCL22/monocyte-derived chemokine in both homeostasis and inflammation. Significantly, CCL22/monocyte-derived chemokine exhibited regulatory effects on CD4+ T cell proliferation. Further functional analysis showed that both DC types induced comparable Th subset development. These studies showed that lung CD11bhigh DC is one of the most important leukocyte types in chemokine production and it is readily distinguishable from CD103+ DC in this secretory function.

Neutrophils Ameliorate Lung Injury and the Development of Severe Disease during Influenza Infection

“…Samples were then treated for a further 5 min with EDTA to disrupt T cell-DC complexes. cDCs were identified as CD11c high , MHC class II high (I-A b ) (17), and pDCs as CD11c int , PDCA-1 ϩ cells (18,19).…”

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

“…Furthermore, respiratory cDCs are preferentially localized in the lung interstitium, and upon activation, these cells produce a range of inflammatory mediators (26,27). A previous study has demonstrated that the inhalation of pathogenic material, such as bacteria or viral particles, induce a very rapid recruitment of DCs into the airways of rodents, in some cases peaking already 2 h after challenge (28).…”

Origin and functional specializations of DC subsets in the lung

“…First, lung CD11b 1 DC massively produce proinflammatory chemokines thus attracting CD4 1 and CD8 1 effector lymphocytes to airways, to mediate effector functions [3]. Legge demonstrated that these CD11b 1 inflammatory DC indeed boost CD8 1 effector activity in the lung [49].…”

“…The function of DC during allergen challenge could be the local restimulation of effector function in lung resident lymphocytes, or alternatively could be the recruitment of these effector Th2 cells [60]. In allergen-challenged mice, CD11b 1 DC are a prominent source of the chemokines CCL17 and CCL22, thus recruiting CCR4 1 Th2 cells to the lungs [3,61]. A recent study employing selective depletion of lung CD11b 1 myeloid cells (most likely CD11b 1 inflammatory DC) in CD11b-DTR mice indeed identified these cells, and not bronchial epithelial cells, as the critical source of CCL17 and CCL22 [62].…”

“…Immediately below, the lamina propria contains CD11b hi cDC [3][4][5] that express the SIRPa molecule (a ligand of CD47), and the CX3CR1 fractalkine receptor [6,7]. The conducting airways also contain pDC, best identified by additional staining for Siglec-H, or bone-marrow stromal antigen-2 (BST2) [1,2,8,9].…”