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Role of cAMP-PDE4b-CREB Signaling in Controlling the Function of Alveolar Macrophages

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posted on 01.08.2021, 00:00 authored by Ian P Rochford
Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Recent studies indicate that AMϕ, the predominant immune cell type in the airspace, die off while fending off pathogens and are replaced by recruited monocytes. These new AMϕ facilitate the resolution of injury, but the mechanisms regulating this reparative phenotype have not yet been defined. Cyclic AMP (cAMP) is an immunosuppressive second messenger in many cell types. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address investigate changes in cAMP signaling in the initiation and mobilization of reparative AMϕ. RNA-seq analysis of flow-sorted Mϕ identified PDE4b as the top LPS-responsive cAMP-regulating gene. We observed that the cAMP negative regulator PDE4b expression sharply increased at the time of peak lung injury (4 h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for transcription of PDE4b in Mϕ. Inhibition of PDE4 activity after injury induction using i.t. rolipram increased cAMP levels, augmented the reparative AMϕ pool, and accelerated injury resolution. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited monocytes as the source of reparative AMϕ following enhanced PDE4 inhibition. Interestingly, adoptive transfer of rolipram-educated AMϕ into injured mice resolved lung edema. The transcription factor CREB was shown to be required for rolipram-induced injury resolution and maintenance of basal lung fluid homeostasis. We propose that enhanced CREB signaling through suppression of PDE4b is an effective approach to promote reparative AMϕ generation from monocytes for lung repair.

History

Advisor

Mehta, Dolly

Chair

Mehta, Dolly

Department

Pharmacology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Komarova, Yulia Pajcini, Konstandin Reddy, Shekhar Kim, Kiwook

Submitted date

August 2021

Thesis type

application/pdf

Language

en

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