Patrick Belvitch, MD
Steven Dudek, MD, ATSF
Dustin Fraidenburg, MD
Jeffrey Jacobson, MD
Irena Levitan, PhD
Viswanathan Natarajan, PhD
Gye Young Park, MD
Sunit Singla, MD
Kevin Haas, MD
Min Joo, MD
Chris Kapp, MD
Kevin Kovitz, MD, MBA
Jerry A. Krishnan, MD, PhD
Marisol Munoz, MSN, FNP-BC
Mary Pasquinelli, DNP, FNP-BC
Bharati Prasad, MD
Israel Rubinstein, MD
Health Services Research
Andrea Pappalardo, MD
GYE YOUNG PARK, MD LAB
Macrophage and Dendritic cell research in lung diseases
Hyung-Geun (Peter) Moon (Ph.D.), a research assistant professor, received the Catalyst Award of the American Lung Association to study the CSF1-CSF1R pathway for allergen sensitization.
Our lab has investigated molecular and cellular mechanisms of immune cells with a more holistic understanding of how these mechanisms work in actual patients. Our studies adopt translational tools based on human samples and apply the data to animal models relevant to human diseases. This approach has resulted in a number of high-quality publications on the phenotypic heterogeneity of immune cells and their transcriptional and posttranslational gene regulation, eventually showing how they modulate pulmonary diseases. More recently, this work has led to an interest in the cellular heterogeneity of macrophages and dendritic cells in asthma. Our lab established the techniques required to analyze the phenotypes and genotypes of innate immune cells, including flow cytometry, sc-RNA-seq, and mass cytometry (CyTOF). To evaluate the clinical relevance of the data from animal models, we run the IRB-approved human translational protocol for bronchoscopic provocation with the sensitized allergen. With the network of collaborators both inside the campus and beyond, our lab will continue to focus on immune cell biology in the lung to understand human lung diseases better.
Selected Key Publications
1. Moon HG, Kim SJ, Jeong JJ, Han SS, Jarjour NN, Lee H, Werner SL, Chung S, Choi HS, Natarajan V, Ackerman SJ, Christman JW, Park GY. Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity. 2018, 49(2):275-287. PMID: 30054206; PMCID: PMC6594049. DOI: https://doi.org/10.1016/j.jaci.2018.09.010.
2. Moon HG, Kim SJ, Lee MK, Kang H, Choi HS, Harijith A, Ren J, Natarajan V, Ackerman SJ, Christman JW, Park GY. Colony stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma. Allergy. 2020 Feb;75(2):357-369. PMID: 31385613; PMCID: PMC7002247.
3. Lee YG, Jeong JJ, Nyenhuis S, Berdyshev E, Chung S, Ranjan R, Karpurapu M, Deng J, Qian F, Kelly E, Jarjour N, Ackerman SJ, Natarajan V, Christman, JW, Park GY. Recruited Alveolar Macrophages, in Response to Airway Epithelial-derived MCP-1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma. Am J Respir Cell Mol Biol. 2015, 52(6):772-84.
4. Park GY, Lee YG, Berdyshev E, Nyenhuis S, Du J, Fu P, Gorshkova IA, Li Y, Chung S, Karpurapu M, Deng J, Ranjan R, Xiao L, Jaffe HA, Corbridge SJ, Kelly EA, Jarjour NN, Chun J, Prestwich GD, Kaffe E, Ninou L, Aidinis V, Morris AJ, Smyth SS, Ackerman SJ, Natarajan V, Christman JW. Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir. Crit. Care Med. 2013, 188(8); 928-940.
5. Kim SJ, Moon HG, Park GY. The roles of Autotaxin/Lysophosphatidic acid in immune regulation and asthma. Biochim. Biophys. Acta Mol Cell Biol. Lipids. 2020 May;1865(5):158641. PMID: 32004685; PMCID: PMC7068735.
Name of the project: Lung-resident dendritic cell type 2 and allergic asthma.
Brief Description: Sensitization against specific aero-allergens such as house dust mites and pollens represents the first step in developing allergic asthma. Sensitized individuals express high immunoglobulin E (IgE) levels against the sensitized allergen(s). Before our study, a consensus existed regarding how sensitization against inhaled allergens occurred. Airway DCs play a key role in taking up and processing inhaled allergens. Subsequently, airway DCs migrate to the regional LN and present the antigen to T- and B-cells to establish allergen-specific IgE production, Th2-mediated allergic inflammation, and allergen-specific memory immunity. Previous studies have shown that cDC2s, but not cDC1 or monocytic DCs, are essential for sensitization against aero-allergens. However, it remained unknown which cDC2 subsets were involved in this process and how cDC2s were activated to recognize inhaled allergens and promote Th2-mediated immunity against inhaled allergens. We previously reported that AECs are master regulators of the airway micro-environmental milieu through the secretion of various chemokines and cytokine, which recruit inflammatory cells and initiate lung inflammation. The current project discovered CSF1 as a new member of epithelium-derived alarmins. We found that allergen-exposed AECs secrete CSF1 into airways in response to inhaled allergen challenges in humans and mice. CSF1 levels in human bronchoalveolar lavage (BAL) were remarkably increased by bronchoscopic provocation with the sensitized allergen. In human BAL cells, we also discovered the existence of alveolar cDCs, which increased in number following bronchoscopic provocation with the sensitized allergen. Our study also revealed that AEC-derived CSF1 binds CSF1R on CSF1R+cDC2s recruited to the airway by allergen exposure. Remarkably, we discovered that CSF1 binding with CSF1R enhanced the expression of CCR7 in the CSF1R+cDC2 subpopulation. CCR7 is a critical molecule in DC migration and subsequent antigen presentation. This finding is consistent with other recent reports showing that CSF1 secreted locally by structural cells regulates the functions and survival of myeloid lineage cells.
In summary, our study showed that AEC-secreted CSF1 regulates the DC-mediated trafficking of aeroallergens and the subsequent development of adaptive immune responses. Our current project made significant contributions to this field by discovering that the specific population of CSF1R+cDC2s serves as the key cDC2 subset involved in allergen sensitization. Our study highlighted that AECs regulate DC functions in airways and showed that DCs bridge innate and adaptive immune responses by mobilizing and presenting allergens to adaptive immune cells.
Name of the project: Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation
Brief Description: Asthma is a major health care burden to patients, families, and societies. The management of asthma is far less than ideal, in part due to our incomplete understanding of cellular and molecular processes of asthmatic inflammation. This project seeks to determine the novel mechanism of the resolution of allergic inflammation, specifically focusing on a specialized cell type that is responsible for clearing inflammatory cells and their debris to facilitate the resolution of inflammation. Recent studies show that tissue-resident macrophages participate in not only the initiation of inflammation but also in the resolution and prevention of local inflammation. To precisely determine the subsets of macrophages engaged in resolving lung inflammation and gain insight into their functions, we adopt new techniques of mass cytometry and single-cell RNA-seq (sc-RNA-seq) to analyze human and mouse macrophages in the lung. Our data showed that pulmonary macrophages (PMs) are phenotypically diverse and highly dynamic in response to allergen challenge. Based on the sc-RNA-seq data, PMs can be clustered into a few groups at a steady status. Among these groups, a subset of CX3CR1-expressing PMs (CX3CR1+ AMs) is unique in terms of their phenotype and patterns of gene expression, compared to classical resident AMs. In patients with allergic asthma and a mouse model of asthma, we found that CX3CR1+ AMs are markedly increased in BAL by allergen challenge. Further investigation with the CX3CR1- reporter and Epx-cre (a.k.a. Eo-cre) reporter mice reveals that CX3CR1+ macrophages engulf eosinophils at a steady state and in allergic lung inflammation. Regarding the molecular mechanism of CX3CR1+ mediated-eosinophil clearance, we discovered that CCL26 plays a key role in activating CX3CR1+ macrophages, whereas CX3CL1 is indispensable. This project is based on our strong supporting data on the new roles of CX3CR1+ macrophages in the resolution of allergic lung inflammation.
Name of the project: CSF1 Receptor-Mediated Tumor Microenvironment in Lung Cancer
Brief Description: Thanks to the collaborative efforts of immunologists and oncologists, cancer immunotherapy and its immunologic research made clinical and scientific breakthroughs in the treatment of lung cancer. Our lab investigates the role of tumor-infiltrating myeloid cells such as macrophages and dendritic cells (DCs) and seeks a new approach for myeloid cell-mediated cancer immunotherapy. The microenvironmental milieu determines the phenotype of myeloid cells. Our lab reported that Colony Stimulating Factor 1 (CSF1), one of key mediators of the microenvironment, is critical for determining the immunologic function of a DC subset. It has been well known that tumor cells secrete CSF1 to alter their microenvironment, yet the mechanism of action is not fully elucidated. In ongoing clinical trials, several agents targeting CSF1 receptor (CSF1R) are being tested for cancer treatment. In this project, we study a new role of tumor-produced CSF1 in altering tumor immune microenvironment toward tumor progression by producing autotaxin (ATX) which increases the number of protumoral myeloid cells such as macrophages and DCs. ATX, also known as lysophospholipase D, is secreted extracellularly and enzymatically generates lysophosphatidic acid (LPA), the most abundant phospholipid in body fluid. LPA is well known to stimulate cellular proliferation, migration, and survival for myeloid lineage cells. The project is based on our two new critical discoveries on myeloid cell biology; (1) ATX is highly expressed in myeloid cells under the control of CSF1 and its receptor (CSF1R) activation, (2) ATX regulates the size of the residential population of lung myeloid cells in the CSF1R-dependent manner (CSF1R-ATX pathway). Together these findings have led to the hypothesis that tumor-produced CSF1 stimulates protumoral myeloid cells to secrete ATX to increase the number of protumoral macrophages and DCs. To validate the hypothesis, we employ the approaches for proof-of- concept by utilizing the novel transgenic mice that have the loss or excess of the target genes. The clinical arm exploits clinical samples from patients with lung cancer to verify the proof-of-concept. Lastly, in the translational arm, we examine the therapeutic potentials of interfering CSF1R-ATX pathway in the mouse lung cancer model by adopting a state-of-art nano-delivery system.
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