Respiratory mononuclear phagocytes during steady state and sarcoidosis

Each day, our lungs inhale thousands of liters of air containing not only essential oxygen but also smoke particles, dust, allergens, and potentially dangerous pathogens. In order to tolerate harmless antigens and initiate an immune response against pathogens, a well-organized network of immune cells is required in the respiratory tract. Mononuclear phagocytes (MNPs), comprised of macrophages, monocytes, and dendritic cells, line the respiratory mucosa and are equipped with tools to recognize and rapidly respond to foreign materials. Despite MNPs act as sentinels at the mucosal barrier, infections and inflammation can affect the lungs. Pulmonary sarcoidosis is a T cell-driven inflammatory disease characterized by granuloma formation. The causative antigen is yet to be identified but MNPs are known to be involved in the pathogenesis of sarcoidosis. A theory is that the antigen is taken up by macrophages. Macrophages also produce vast amounts of the proinflammatory cytokine tumor necrosis factor (TNF). Dendritic cells on the other hand, take up the antigen and transport it to the lymph nodes where they activate naïve T cells. Circulating monocytes have an important role in cytokine production. However, the role of respiratory monocytes during sarcoidosis is less well studied. We hypothesized that pulmonary MNPs are crucial in maintaining a steady state of antiand pro-inflammatory processes in healthy individuals. This dynamic process is disturbed during sarcoidosis, thereby contributing to pathogenesis. Hence, our aim was to study MNPs in the respiratory tract during steady state and sarcoidosis.

First, we investigated MNPs in the human respiratory tract. We found profound differences in distribution of seven MNP subsets between blood and the respiratory tract both during steady state and sarcoidosis. We observed an increase in frequencies of blood and respiratory monocytes in sarcoidosis patients compared to healthy controls. Additionally, monocytes from sarcoidosis patients showed an inflammatory profile with upregulation of genes related to inflammatory pathways. Intriguingly, MNPs from the lungs of sarcoidosis patients produced TNF without external stimulation to a significantly higher degree than that of MNPs from healthy controls. In contrast to previous observations, we found that pulmonary monocytes contributed more to TNF production than macrophages. Additionally, we associated higher frequencies of monocytes in the circulation as well as high numbers of intrinsically TNF producing monocytes at time of diagnosis with progressive disease development in sarcoidosis.

In conclusion, we have mapped the MNP network in several anatomical locations of the respiratory tract during steady state and sarcoidosis. We also identified pulmonary monocytes to play an important role in disease pathogenesis in sarcoidosis. That knowledge can help to design new treatment options in sarcoidosis to favor disease resolution and improve quality of life.

List of scientific papers

I. Faezzah Baharom, Saskia Thomas, Gregory Rankin, Rico Lepzien, Jamshid Pourazar, Annelie F. Behndig, Clas Ahlm, Anders Blomberg, and Anna Smed-Sörensen. Dendritic cells and monocytes with distinct inflammatory responses reside in lung mucosa of healthy humans. Journal of Immunology. 2016, 196(11): 4498-509.
https://doi.org/10.4049/jimmunol.1600071

II. Rico Lepzien, Gregory Rankin, Jamshid Pourazar, Ala Muala, Anders Eklund, Johan Grunewald, Anders Blomberg, and Anna Smed-Sörensen. Mapping mononuclear phagocyte in blood, lungs and lymph nodes of sarcoidosis patients. Journal of Leukocyte Biology. 2019; 105:797-807.
https://doi.org/10.1002/JLB.5A0718-280RR

III. Rico Lepzien, Sang Liu, Paulo Czarnewski, Mu Nie, Björn Österberg, Faezzah Baharom, Jamshid Pourazar, Gregory Rankin, Anders Eklund, Matteo Bottai, Susanna Kullberg, Anders Blomberg, Johan Grunewald, and Anna Smed-Sörensen. Monocytes in sarcoidosis are potent TNF producers and predict disease outcome. [Manuscript]

IV. Rico Lepzien, Mu Nie, Sang Liu, Avinash Ravindran, Susanna Kullberg, Anders Eklund, Johan Grunewald, and Anna Smed-Sörensen. Blood and BAL dendritic cells from sarcoidosis patients induce IFNγ producing Th1 cells. [Manuscript]