Impact of aging on immune function in the pathogenesis of pulmonary diseases: potential for therapeutic targets

Abstract

Introduction: Several immunological alterations that occur during pulmonary diseases often mimic alterations observed in the aged lung. From the molecular perspective, pulmonary diseases and aging partake in familiar mechanisms associated with significant dysregulation of the immune systems. Here, we summarized the findings of how aging alters immunity to respiratory conditions to identify age-impacted pathways and mechanisms that contribute to the development of pulmonary diseases.

Areas covered: The current review examines the impact of age-related molecular alterations in the aged immune system during various lung diseases, such as COPD, IPF, Asthma, and alongside many others that could possibly improve on current therapeutic interventions. Moreover, our increased understanding of this phenomenon may play a primary role in shaping immunomodulatory strategies to boost outcomes in the elderly. Here, the authors present new insights into the context of lung-related diseases and describe the alterations in the functioning of immune cells during various pulmonary conditions altered with age.

Expert opinion: The expert opinion provided the concepts on how aging alters immunity during pulmonary conditions, and suggests the associated mechanisms during the development of lung diseases. As a result, it becomes important to comprehend the complex mechanism of aging in the immune lung system.

Keywords: Aging; COPD; Cellular senescence; Cytokines; IPF; Immunity; Lymphocytes.

Figure 1:. Aging impacts the immune responses on the occurrence of chronic pulmonary diseases:

Aging causes dysregulation in the immune system which further leads to reduced production of naive T and B cells, Also, augments CD4+ cells which elevates Th17 cells differentiation activating pro-inflammatory molecules. In addition, expanding CD8+ cells lead to CD28+ cells. These immune targets further get accumulated in the lungs resulting in decreased migration to antigen encounter regions and promoting the development and pathogenesis of chronic lung disease.

Figure 2:. The consequences of lung aging on the immune response against COPD: An COPD-aged lung experience.

(A) Impaired innate and adaptive immunity. Lung Aging decreases the T and B cell response, which declines the responses of both CD4+ and CD8+ T cell responses. Reduced B cell responses cause diminished generation of protective antibodies. (B) Dysregulated inflammation leads to alterations in inflammatory molecules in the lungs during COPD. Increased levels of cytokines (IL-6, TNF-α, IFN--γ) lead to increased recruitment of neutrophils causing an increase in neutrophil infiltration and impairing their ability to phagocytose neutrophils and debris. Lung aging causes increased numbers of NK cells, and DAMPs elevate inflammation and enlarge airspace by causing the decline in lung function.

Figure 3:. A schematic description of the immune cell’s mechanism in IPF aged: IPF-aged lungs cause the reduced T-Cell response.

Alveolar macrophages expand fibrosis via altering characteristics in response to activation of various inflammatory mediators resulting in ECM deposition which promotes the production of TGF-β1, MMPS and TIMPS followed by a decline in collagen XIV levels along with decorin which is its binding partner. ECM deposition further leads to alterations in epigenetic alterations, telomere shortening, genomic instability, mitochondrial dysfunction, and impaired autophagy. These pro-fibrotic and pro-inflammatory changes further regulate fibroblast accumulation.

Figure 4:. Immune mechanism in asthma due to lung aging:

Disturbance of the epithelium due to allergens during lung aging in asthma condition activates innate signaling receptors, leading to secretion of chemokines like CCL-22 and CXCL-8 from airway epithelial cells and trafficking of immature Dendritic xells to the mucosal secretion. Dendritic Cells mature and process the allergens encountered through the airways, or by triggering allergens that have raptured the epithelium. The allergen stuffed dendritic cells then interact with naive Th2 cells and then drive the differentiation of Th2 cells. Additionally, neutrophils and dendritic cells activate epithelial-derived cytokines and chemokines, such as IL-1β, IL-4, IL-13, CXCL-8 and CCL-22 upregulated levels of TLR-2 and TLR-4 influences Dendritic cell activation and T_H2 maturation and emigration into the mucosa. Neutrophils on aging during asthma lead to impaired phagocytosis, increase serine proteases activity, and also enhance neutrophil α-defensins.