Author ORCID Identifier
0000-0002-6679-7599
Date of Graduation
12-2024
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
<-- Please Select One -->
Advisor/Committee Chair
Stephanie S. Watowich, Ph.D.
Committee Member
Robert R. Jenq, M.D.
Committee Member
Michael A. Curran, Ph.D.
Committee Member
Roza I. Nurieva, Ph.D.
Committee Member
Jennifer Lundberg, Ph.D.
Abstract
The localized signals that bone marrow (BM) hematopoietic stem cells (HSCs) and immune cells receive are critical in regulating their responses in the steady state and inflammation. Monocytes are an abundant and key population in the innate immune response that originates in the BM, and they circulate to monitor the periphery. Monocytes are composed of many subsets that have essential and specific functions, including swift egress from the BM, production of pro-inflammatory cytokines, and differentiation into monocyte-derived dendritic cells (MoDCs), which are required for efficient pathogen eradication.
Here, we uncovered LIFR (leukemia inhibitory factor receptor) restrains low-grade chronic inflammation in the BM by restraining STAT1 signals. LIFR deletion in CD11c-expressing cells resulted in reduced frequency of BM long-term (LT) HSC, increased the frequency of circulating myeloid populations and enhanced MHC-II expression in BM monocytes.
We identified an important function of the LIFR in monocyte development and response to inflammatory challenges. Using mice with conditional deletion of LIFR in CD11c+ cells (CD11c-cre Lifrf/f mice), we find LIFR prevents abnormal activation of type I interferon (IFN-I) signaling in BM monocytes, which is accompanied by an increased activation phenotype and altered transcriptional state in homeostasis. Additionally, we observed that LIFR is required to limit anomalous BM HSC proliferation. Yet, upon challenge with lipopolysaccharide (LPS), monocytes in CD11c-cre Lifrf/f mice fail to upregulate maturation markers, have defective accrual in blood, and show impaired differentiation into MoDCs.
We found that the functional LIFR is uniquely enriched in plasmacytoid dendritic cells (pDCs), while pDCs and monocytes show specific deregulation of IFN-I signaling in CD11c-cre Lifrf/f mice. Our data reveal a novel role for LIFR in controlling monocyte homeostasis and response to inflammation and further suggest this occurs by modulation of tonic IFN-I production in the BM.
Keywords
Leukemia inhibitory factor receptor, pDCs, monocytes, STAT1, inflammation