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  • br Future direction and conclusion br Conflict of interest


    Future direction and conclusion
    Conflict of interest
    References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
    Introduction Colony stimulating factor-1 (CSF-1; also referred to as the macrophage-colony stimulating factor) is the primary regulator of proliferation, differentiation, and survival of macrophages and their precursors (Barreda et al., 2004). It also controls key aspects of macrophage function including microbicidal activity (O\'Mahony et al, 2008, Roilides et al, 1996), cytokine (Chitu, Stanley, 2006, Evans et al, 1995) and chemokine (Hashimoto et al, 1996, Sweet, Hume, 2003) production, chemotaxis (Boocock et al, 1989, Webb et al, 1996), and phagocytosis (Akagawa, 2002, Cheers et al, 1989). This is a testament to its broad importance to the regulation of host immunity. However, CSF-1 has also been linked to numerous pathological conditions, including but not limited to, allograft and xenograft rejection, cancer, autoimmune disorders, atherosclerosis, and obesity (Chitu, Stanley, 2006, Kleemann et al, 2008, Lewis, Pollard, 2006, Menke et al, 2009, Rubin Kelley et al, 1994, Weisberg et al, 2003). As such, tight regulation of CSF-1 activity is critical to foster its beneficial immune-regulatory responses while minimizing the potential for deleterious outcomes. CSF-1 exerts its biological effects at nanomolar concentrations and several mechanisms have evolved to regulate its actions, including receptor-mediated endocytosis, metabolic processing and the inhibition of downstream signaling (Barreda et al, 2004, Rieger et al, 2014). CSF-1 activity is also regulated through intracellular modulation of gene MHY1485 of both CSF-1 and its cognate receptor CSF-1R (Barreda et al, 2004, Rieger et al, 2014). Most recently, we identified a unique mechanism for regulation of CSF-1 activity in teleost (bony) fish. These fish produce a novel soluble form of CSF-1 receptor (sCSF-1R), which decreases macrophage proliferation in a dose-dependent manner (Barreda, Belosevic, 2001, Barreda et al, 2005). The native protein was detected in goldfish serum (Barreda et al., 2005), providing early suggestions that this protein might play a role in systemic regulation of CSF-1 activity. With this in mind, we investigated the role of sCSF-1R in the regulation of teleost macrophage antimicrobial responses. In vitro, we found that soluble CSF-1R inhibited CSF-1-mediated reactive oxygen production, nitric oxide synthesis, chemotaxis, and phagocytosis in cultured macrophages (Grayfer et al., 2009). Further, in vivo experiments showed that this novel soluble protein inhibited zymosan-driven leukocyte infiltration and ROS production in a dose-dependent manner (Rieger et al., 2013). In this study, we focused on the sCSF-1R-driven mechanisms that control neutrophil responses at a site of inflammation. We found that sCSF-1R inhibited neutrophil recruitment in vivo through downregulation of CXCL-8 expression, resulting in reduced neutrophil chemotaxis. Soluble CSF-1R also decreased expression of several pro-inflammatory cytokines that are well known to promote neutrophil activation and antimicrobial responses. Characterization of functional responses from inflammatory neutrophils showed a reduced capacity for phagocytosis and intracellular pathogen killing following intraperitoneal administration of sCSF-1R. Importantly, the contributions of sCSF-1R to the inhibition of neutrophil inflammatory responses showed marked similarities to those elicited by apoptotic cells (AC), implicating sCSF-1R as an important component of AC-driven inhibition of inflammation. However, broader contributions of AC to the global regulation of cytokine gene expression suggest that factors beyond sCSF-1R also contribute to the resolution phase of inflammation in this teleost fish.
    Materials and methods
    Discussion Inflammation is an important physiological process for the clearance and control of pathogens. However, a loss or untimely control of inflammation can have grave consequences for the host since it can contribute to the development of chronic inflammatory diseases, autoimmunity, and chronic infection (Duffield, 2003, Poon et al, 2010, Soehnlein, Lindbom, 2010). Macrophages and their central regulator, CSF-1, have been tightly linked to both the beneficial and deleterious effects of inflammation (Chitu and Stanley, 2006). As such, the CSF-1 regulatory system represents an important node for the control of inflammation. Yet, almost 40 years after the original discovery of CSF-1, we continue to identify new strategies for control of CSF-1 activity and become increasingly aware of the potential positive and negative repercussions if it is to be used as a therapeutic target. In this manuscript we add to the evolutionary insights into the regulation of CSF-1 activity using a teleost fish model.