Dendritic Cells (DCs)

Professional, antigen presenting DCs play a critical role in linking innate and adaptive immunity. Lung DCs are categorized as conventional DCs (cDCs), plas- macytoid DCs (pDCs) and monocyte-derived DCs (moDCs) each representing independent developmental lineages. Lung DCs develop in the bone marrow and enter the lung as pre-DCs that are thought to differentiate locally into mature DC subsets [30]. Although changes in pattern recognition and toll-like receptor expressions have not yet been reported during ageing in lung DCs, antigen uptake by pinocytosis has been shown to be less effective and cytokine expression profiles alter so that instead of Th1, they promote Th2-type T-cell responses [31]. Such a skewed response may help responses to extracellular infections but may dampen Th1 inflammatory responses to intracellular pathogens such as respiratory viruses.

Macrophages

Tissue macrophage subsets, including lung alveolar macrophages (AMs) , often arise from embryonic progenitors that seed the organs and mature locally before and shortly after birth [31]. GM-CSF instructs lung foetal monocyte differentiation shortly before and after birth through activation of the nuclear receptor PPARy [32]. Deletion of PPARy in AMs of experimental animals resulted in pulmonary alveolar proteinosis (PAP) a process seen in patients with PAP who have low expression of PPARy in AMs. AMs are maintained by proliferative self-renewal throughout life autonomously, independent from bone marrow-derived monocytes. It has been established that AMs suppress immune responses through the inhibition of DC-mediated activation of T cells and production of transforming growth factor p (TGFp). Recent studies have also shown that TGFp-induced Foxp3+ Treg cells (iTreg cells) inhibit spontaneous and antigen-induced development of Th2-type airway inflammation and induce tolerance to inhaled innocuous antigens [33]. The process is AM- and not DC-dependent and occurs in the lung tissue, not in the draining lymph nodes. In AMs, the switch from a tolerogenic mode to an inflammatory mode is accompanied by the secretion of IL-1, IL-6, TNFa and a latent TGFp secretion where the latter only becomes activated by the integrin aVp6 expressed on alveolar epithelial cells (AECs). In the absence of aVp6 on epithelial cells spontaneous inflammation and emphysema develop [34]. Data indicate that detachment of AMs from epithelia upon infection may unleash AM inflammation by withdrawal of active TGFp. Inhibition of pathological airway inflammation occurs via the intercommunication of AMs located in alveoli through the alveolar epithelium communication. The prevention of inflammatory responses is mediated by various inhibitory receptors on AMs, with the ligands expressed on AECs or present in the alveolar fluid [35].

With respect to ageing, recent studies resulted in controversial data when investigating senescent macrophages. In mouse studies some differences in TLR expression and cytokine responses as well as differentiation from macrophage progenitors were detected, but these have not all been observed or even investigated in human ageing studies. Nevertheless, aged macrophages exhibit low-grade pro-inflammatory phenotype and significantly reduced levels of autophagy that contribute to accelerated changes in the ageing process in general [36i . Unfortunately, little is known about specific changes characteristic to human alveolar or bronchial resident macrophages with age.

 
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