Differential regulation of lung homeostasis and silicosis by the TAM receptors MerTk and Axl.

Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the in vivo function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

Efferocytosis in lung mucosae: implications for health and disease.

Efferocytosis is imperative to maintain lung homeostasis and control inflammation. Populations of lung macrophages are the main efferocytes in this tissue, responsible for controlling immune responses and avoiding unrestrained inflammation and autoimmunity through the expression of a plethora of receptors that recognize multiple 'eat me' signals on apoptotic cells. Efferocytosis is essentially anti-inflammatory and tolerogenic. However, in some situations, apoptotic cells phagocytosis can elicit inflammatory and immunogenic immune responses. Here, we summarized the current knowledge of the mechanisms of efferocytosis, and how any abnormality in this process may have an important contribution to the lung pathophysiology of many chronic inflammatory lung diseases such as asthma, acute lung injury, chronic obstructive pulmonary disease, and cystic fibrosis. Further, we consider the consequences of the dual role of efferocytosis on the susceptibility or resistance to pulmonary microbial infections. Understanding how efferocytosis works in different contexts will be useful to the development of new and more effective strategies to control the diversity of lung diseases.