Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

STAT1-Regulated Lung MDSC-like Cells Aid Resolution of Inflammation After Bacterial Pneumonia

Poe, Stephanie L. (2012) STAT1-Regulated Lung MDSC-like Cells Aid Resolution of Inflammation After Bacterial Pneumonia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (8MB) | Preview


We have recently identified a CD11b+Gr1intF4/80+ (Gr1int) regulatory, non-migratory, cell type in the lung that is able to suppress a Th2 effector response via secretion of Interleukin-10 (IL-10), arginase 1 (Arg1) and nitric oxide (NO). These regulatory lung Gr1int cells also secrete Interleukin-6 (IL-6) and Granulocyte macrophage-colony stimulating factor (GM-CSF), but low levels of Interleukin-12 (IL-12). Our studies show that although Gr1int cells are present in the lung of naïve mice, their frequency increases in the interstitium following endotoxin/lipopolysaccharide (LPS) exposure in a TLR4/MyD88-dependent fashion. The suppressive function of these Gr1int cells is significant in the context of allergic inflammation, and because this suppressive cell type accumulates in the lung in response to a bacterial cell wall component, they may be a mechanism underlying the hygiene hypothesis, which was postulated in 1989 to describe the observation that despite increased sanitation in westernized countries, the prevalence of allergies is steadily increasing. Because of the potent suppressive capacity of lung Gr1int, they are now recognized as lung myeloid derived suppressor cells (lung-MDSCs)1. We sought to gain a better understanding of their development to allow for improved therapeutic targets during allergic inflammation.

Secondly, the rapid appearance of these cells in response to a TLR ligand, combined with their non-migratory nature and their anatomical location in the lung interstitium, suggests a unique function during host defense against bacterial infections. Much is already known about the role of alveolar macrophages and neutrophils in host defense against Klebsiella pneumoniae, but little is known about host defense mechanisms in the lung tissue/interstitium. Therefore, we have also examined the role of MDSC-like cells in defense against K. pneumoniae.

Briefly, although an inflammatory response in the lung is required to fight the causative agent, persistent tissue-resident neutrophils can induce collateral tissue damage and precipitate acute lung injury during non-resolving pneumonia. Little is known about mechanisms orchestrated in the lung tissue that remove apoptotic neutrophils to restore tissue homeostasis. We show that these MDSC-like cells increase following exposure to K. pneumoniae, are able to efferocytose apoptotic neutrophils and are a major source of IL-10 in the lung late after infection. Furthermore, using IL-10-/- mice, we show that IL-10 is critical for the control of neutrophilia and restoration of homeostasis. Finally, because IFNγ-STAT1 signaling is known to inhibit IL-10, we examined the lungs of STAT1-/- mice. The lung neutrophil burden was attenuated in infected STAT1-/- mice with concomitant increase in the frequency of the MDSC-like cells and lung IL-10 levels. Thus, inhibiting STAT1 in combination with antibiotics may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia. The inhibition of STAT1 may also be relevant in the context of allergic inflammation when a greater immunosuppressive force, or increased numbers of lung MDSCs, would be advantageous to temper lung inflammation.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Poe, Stephanie
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRay, Anuradharaya@pitt.eduRAYA
Committee MemberRay, Prabirrayp@pitt.eduRAYP
Committee MemberLarregina, Adrianaadrianal@pitt.eduADRIANAL
Committee MemberMonga, Paulsmonga@pitt.eduSMONGA
Committee MemberThomson, Angusthomsonaw@upmc.eduATHOMSON
Committee MemberVyas,
Date: 28 June 2012
Date Type: Publication
Defense Date: 21 June 2012
Approval Date: 28 June 2012
Submission Date: 27 June 2012
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 137
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Immune Regulation Myeloid Cells Interleukin-10 Lung Biology Pneumonia STAT1
Date Deposited: 28 Jun 2012 15:55
Last Modified: 19 Dec 2016 14:38


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item