Effect of LysM+ macrophage depletion on lung pathology in mice with chronic bronchitis.

Yogesh Saini,Wanda K O'Neal,Fabio Del Piero,Dongfang Yu,Richard C Boucher,Hong Dang,Alessandra Livraghi-Butrico,Brandon W Lewis

doi:10.14814/phy2.13677

Yogesh Saini, Wanda K O'Neal + Show 6 more

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https://doi.org/10.14814/phy2.13677

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Abstract

Macrophages (MΦ) are key sentinels of respiratory exposure to inhaled environmental stimuli. In normal “healthy” tissues, MΦ are believed to be a dormant cell type that, upon exposure to stress‐causing stimuli, may get activated to exhibit pro‐ or anti‐inflammatory roles. To test whether stress present in chronic bronchitic (CB) airways triggers MΦ to manifest protective or detrimental responses, the DTA+ (LysM‐regulated Diphtheria Toxin A expressing) strain with partial MΦ‐deficiency was crossed with the Scnn1b‐Tg mouse model of CB and the progenies were studied at 4–5 weeks of age. Compared with DTA− littermates, the DTA+ mice had ~50% reduction in bronchoalveolar lavage (BAL) MΦ, and the recovered MΦ were immature, phenotypically distinct, and functionally defective. DTA+/Scnn1b‐Tg mice exhibited a similar depletion of LysM+ MΦ offset by a significant increase in LysM‐ MΦ in the BAL. In DTA+/Scnn1b‐Tg mice, lung disease was more severe than in DTA−/Scnn1b‐Tg littermates, as indicated by an increased incidence of mucus plugging, mucous cells, airway inflammation, higher levels of cytokines/chemokines (KC, TNF‐α, MIP‐2, M‐CSF, IL‐5, and IL‐17), and worsened alveolar airspace enlargement. DTA+/Scnn1b‐Tg mice exhibited increased occurrence of lymphoid nodules, which was concomitant with elevated levels of immunoglobulins in BAL. Collectively, these data indicate that numerical deficiency of MΦ in stressed airspaces is responded via compensatory increase in the recruitment of immature MΦ and altered non‐MΦ effector cell‐centered responses, for example, mucus production and adaptive immune defense. Overall, these data identify dynamic roles of MΦ in moderating, rather than exacerbating, the severity of lung disease in a model of CB.

Highlights

A balanced composition of immune cells in the respiratory tract is critical to normal host defense and responses to disease
Flow cytometric evaluation of mTom and mEGFP expressing cells was performed on bronchoalveolar lavage (BAL) cells harvested from mice expressing LysM-Cre alone (Clausen et al 1999), ROSA-mTom/mEGFP alone (Muzumdar et al 2007), or both transgenes (Fig. 1; Fig. S2)
To understand the roles of MΦ in the muco-obstructive lung disease in Scnn1b-Tg mice, we conducted a study of neonatal Scnn1b-Tg with and without DTA-mediated MΦ depletion (Saini et al 2015)

Summary

Introduction

A balanced composition of immune cells in the respiratory tract is critical to normal host defense and responses to disease. Numerical or functional deficiencies of macrophage (MΦ) populations in the airspaces (airway and alveolar) of normal lungs is predicted to modulate host defense responses associated with pathogen invasion, environmental toxicants exposure, and intrinsic or genetic defects. A detailed understanding of complex interactions between airspace MΦ and disease severity in chronic a 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society

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