Laura Maria Kahn Serrudo, BS (Advisor: Stephanie S. Watowich, PhD)

The Role of LIFR Signaling in Innate Immunity

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 bone marrow (BM), production of pro-inflammatory cytokines, and differentiation into monocyte-derived dendritic cells (MoDCs), which are required for efficient pathogen eradication.

Here, we identified an important function of the leukemia inhibitory factor receptor (LIFR) in monocyte development and response to inflammatory challenges. Using mice with conditional deletion of LIFR in CD11c⁺ cells (CD11c-cre Lifr^f/f mice), we find that 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 Lifr^f/f mice fail to upregulate maturation markers, have defective accrual in blood, and show impaired differentiation into MoDCs.

In this work, we uncovered that LIFR restrains low-grade chronic inflammation since its deletion in CD11c-expressing cells results in the reduction of the BM long-term (LT)-HSC compartment, higher frequency of circulating myeloid populations and enhanced MHC-II expression in BM monocytes.

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 Lifr^f/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.

Advisory Committee:

• Stephanie S. Watowich, PhD, Chair
• Jennifer M. Bailey-Lundberg, PhD
• Michael A. Curran, PhD
• Rpbert R. Jenq, MD
• Roza I. Nurieva, PhD 

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