The role of inflammatory cells in sarcoidosis and asthma

Immuno-homeostasis refers to maintaining a delicate balance between immune responses and tolerance. It relies on the harmonious interplay of various inflammatory cells, including macrophages, monocytes, dendritic cells, T cells, mast cells, etc. These cells maintain immune surveillance and response mechanisms, ensuring effective defense against pathogens while preventing excessive inflammation, and minimizing tissue damage. The respiratory system faces unique challenges in maintaining immune homeostasis due to constant exposure to airborne particles, allergens, and pathogens. Disruption of respiratory immune homeostasis may lead to chronic inflammatory disorders such as sarcoidosis and asthma, leading to impaired lung function. This thesis delves into the role of inflammatory cells in the pathogenesis of pulmonary sarcoidosis and allergic asthma.

The first part focuses on elucidating the distribution, transcriptional profiles, and functions of mononuclear phagocytes (MNPs) in pulmonary sarcoidosis. Analysis revealed an elevation of CD14+CD16+ monocytes/monocyte-derived cells in the blood and bronchoalveolar lavage cells of sarcoidosis patients. RNA sequencing revealed markedly pro-inflammatory profiles in MNPs from sarcoidosis patients compared to those from healthy controls. Particularly, monocytes/monocyte-derived cells exhibited heightened expression of genes associated with inflammation and TNF signaling. Notably, TNF production by pulmonary monocytes at diagnosis was predictive of patients at risk of developing severe disease (Paper Ⅰ). Furthermore, respiratory MNPs were found to induce potent pathogenic IFN-γ production by Th1 cells (Paper Ⅱ). These findings highlight the significant contribution of MNPs to sarcoidosis pathogenesis.

The second part aimed to study the role of airway-infiltrating inflammatory cells in allergic asthma pathophysiology. This project hypothesized that airway inflammation in asthma causes phenotypic alterations of the resident mast cells and the airway smooth muscle cells. Firstly, monensin was identified as an effective approach to decreasing mast cell populations and alleviating mast cell-related antigen-induced bronchoconstriction in both guinea pigs and humans. This highlights the pivotal role of mast cell hyperplasia in the development of airway hyperresponsiveness and inflammation in allergic asthma (Paper Ⅲ). Additionally, by overcoming post-mortem bronchoconstriction in guinea pig small airways, the study reveals guinea pig intralobular bronchi closely resembling human respiratory features. Combining this newly established guinea pig intralobular bronchi model with the modified guinea pig asthma in vivo model, it was found that allergic airway inflammation amplified mast cell responses (Paper Ⅳ), providing further insights into the pathophysiology of allergic asthma.

List of scientific papers

I. Lepzien R, Liu S, Czarnewski P, Nie M, Österberg B, Baharom F, Pourazar J, Rankin G, Eklund A, Bottai M, Kullberg S. Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome. European Respiratory Journal. 2021 Jul 1;58(1).
https://doi.org/10.1183/13993003.03468-2020

II. Lepzien R, Nie M, Czarnewski P, Liu S, Yu M, Ravindran A, Kullberg S, Eklund A, Grunewald J, Smed-Sörensen A. Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes. Journal of Leukocyte Biology. 2022 Apr;111(4):857-66.
https://doi.org/10.1002/JLB.5A0321-162R

III. Liu J, Nie M, Dong C, Säfholm J, Pejler G, Nilsson G, Adner M. Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models. Scientific reports. 2022 Nov 7;12(1):18924.
https://doi.org/10.1038/s41598-022-23486-1

IV. Nie M, Liu J, Xiang Y, Wong A, Hendriks E, Nilsson G, Säfholm J, Adner M. Induction of allergic airway inflammation amplifies mast cell response in guinea pig intralobular bronchi. [Manuscript]