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Abstract Number: 1002

Nerve and Airway-associated Tissue Resident Pulmonary Macrophages Limit Infiltration and Alter Phenotype of Infiltrating Monocytes and Fibrocytes to Reduce Pulmonary Fibrosis

Robert Freilich1 and Kamal Khanna2, 1New York University Department of Rheumatology, New York, NY, 2New York University Department of Rheumatology & Microbiology, New York, NY

Meeting: ACR Convergence 2021

Keywords: fibrosis, Monocytes/macrophages, pulmonary

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Session Information

Date: Monday, November 8, 2021

Session Title: Innate Immunity Poster (0992–1006)

Session Type: Poster Session C

Session Time: 8:30AM-10:30AM

Background/Purpose: Macrophages and monocytes are increasingly implicated in the pathogenesis of autoimmune induced pulmonary fibrosis. In addition to the well-recognized classes of tissue resident macrophages alveolar macrophages (AMs) and interstitial macrophages (IMs), recent studies have identified a novel class lung tissue resident macrophage termed CD169+ Nerve and Airway-associated Macrophages (NAMs) whose role in autoimmune pulmonary pathology is unclear. Further, recent studies have demonstrated monocytes playing a critical role in the progression of pulmonary fibrosis. Interestingly, monocytes can be further subdivided into classical, non-classical, intermediate and fibrocytes, that are thought to play a key role in fibrosis/wound healing, but whose exact roles in autoimmune induced pulmonary fibrosis are unknown.

Methods: We utilized the bleomycin-induced murine model of pulmonary fibrosis in C57BL/6 wild-type (WT) mice in combination with transgenic murine models that selectively deplete AMs, NAMs, or both AMs/NAMs upon Intraperitoneal injection of diphtheria toxin (DT). DT injection (1000ng) were given 16 hours prior to bleomycin treatment (2.5u/kg). Mice were sacrificed on days 4, 11, 18 and 42. Lungs were fixed, sectioned and stained for IF or disassociated into a single cell suspension, stained, and analyzed by flow cytometry for both surface and intracellular targets, including a-Smooth Actin (aSMA)/Collagen-1a (Col1a).

Results: Bleomycin-treated mice whose NAMs were depleted were sicker than WT littermates, with greater weight loss (34% vs. 24%), reduced survival (35% vs 65%) and increased lung dry weight (67.7mg vs 55.9mg) Interestingly, NAM depletion resulted in increased monocytic infiltration compared to WT bleomycin-treated littermates. We further characterized the infiltrating monocytic compartment, via flow cytometry, as either ‘true’ monocytes (CD45+,CD11b+,CD140a-,SMA-,Col1a-), putative fibrocytes (CD45+,CD11b+,CD140a+,aSMA+, Col1a+) or a transitioning population (CD45+,CD11b+,CD140a+,aSMA+, Col1a-). Our analyses demonstrates that depletion of NAMs alters the infiltrating monocytic compartment in two key ways. First, we observed a 39% increase in the numbers of infiltrating monocytes that are (CD45+,CD11b+,CD140a-) (p=0.0195). However, these monocytes were noted to have more fibrocytic phenotype with higher levels of aSMA or Col1a expression, 23% (aSMA+/Col1a-) (p=0.0426), and 16% (aSMA+/Col1a+) (p=0.0292).

Conclusion: Depleting tissue-resident macrophages led to an increase in infiltrating monocytes skewed towards a more pro-fibrotic phenotype and resulting in a poorer clinical outcome. Taken together, these findings potentially provide insight into the mechanisms of inflammatory pulmonary fibrosis in autoimmune diseases.


Disclosures: R. Freilich, None; K. Khanna, None.

To cite this abstract in AMA style:

Freilich R, Khanna K. Nerve and Airway-associated Tissue Resident Pulmonary Macrophages Limit Infiltration and Alter Phenotype of Infiltrating Monocytes and Fibrocytes to Reduce Pulmonary Fibrosis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/nerve-and-airway-associated-tissue-resident-pulmonary-macrophages-limit-infiltration-and-alter-phenotype-of-infiltrating-monocytes-and-fibrocytes-to-reduce-pulmonary-fibrosis/. Accessed January 28, 2023.
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