Macrophages in Tissue Inflammation and Resolution
The transition from inflammation to resolution is critical for the restoration of tissue function following injury or infection. Tissue resident macrophages (TRM) are key initiators of inflammation through the release of cytokines that recruit neutrophils and other inflammatory leukocytes to the damaged tissue. TRM also play a vital role in resolving inflammation by clearing dead cells and producing pro-resolving mediators that stimulate wound healing and restoration of tissue homeostasis. This functional plasticity is a defining property of macrophages and one that holds great therapeutic promise for treating inflammation-related diseases. Ongoing projects in our lab in this area include: 1) Identification of novel molecular and cellular signals that trigger pro-resolution phenotypes in TRM during inflammation, 2) Determining the role of apoptotic cell clearance (“efferocytosis”) in regulating macrophage transition from pro-inflammatory to pro-resolution, and 3) Determine the long-term effects of tissue inflammation on the immune phenotype and function of TRM using novel computational approaches to identify unique TRM populations associated with long-term resolution of tissue inflammation. The outcome of this research will provide novel insights into the basic mechanisms that underlie immunomodulation by efferocytosis which in turn will provide the mechanistic foundation and investigative tools to develop novel therapies that modulate efferocytic pathways to either enhance the resolution of inflammation (e.g. autoimmunity, sepsis) or activate beneficial immune responses (e.g. anti-tumor immunity, compensatory anti-inflammatory response syndrome).
Measuring in vivo clearance of dying cells by tissue-resident macrophages. ImageStream analysis of fluorescently labeled necrotic murine thymocytes (CMTMR(red)) engulfed by peritoneal macrophages (F4/80). Target internalization is determined using antibodies against thymocyte antigen Thy1.2(pink).
Murphy PS, Wang J, Bhagwat SP, Munger JC, Janssen WJ, Wright TW, Elliott MR. CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages. Cell Death Differ. 2017 Mar;24(3):559-570. PubMed PMID: 28060378; PubMed Central PMCID: PMC5344214.
Elliott MR, Koster KM, and Murphy PS. Brief Review: Efferocytosis signaling in the regulation of macrophage inflammatory responses. Journal of Immunology, 198:1387 (2017). PubMed PMID: 28167649; PubMed Central PMCID: PMC5301545.