Abstract
Microglia are the principal resident innate immune cells of the CNS. Their contributions to the normal development of the CNS, the maintenance and plasticity of neuronal networks and the safeguarding of proper functionality are becoming more and more evident. Microglia also survey the tissue homeostasis to respond rapidly to exogenous and endogenous threats, primarily with a protective outcome. However, excessive acute activation, chronic activity or an improper adaptation of their functional performance can foster neuropathologies. A key to the versatile response behavior of these cells is their ability to commit to reactive phenotypes, which reveal enormous complexity. Yet the respective profiles of induced genes and installed functions may build up on heterogeneous contributions of cellular subsets. Here, we discuss findings and concepts that consider the variety of microglial activities and response options as being based—at least in part—on a diversity of the engaged cells. Whether it is the production of proinflammatory cytokines, clearance of tissue debris, antigen presentation or the ability to sense neurotransmitters, microglial cells present with an unanticipated heterogeneity of their constitutive and inducible features. While the organizational principles of this heterogeneity are still largely unknown, functional implications are already perceptible.
Highlights
Microglia are the principal resident innate immune cells of the CNS
Based on extraneural macrophages, reactive phenotypes were defined by triggering responses to cytokines and microbial agents, such as interferon-γ (IFNγ) from T helper cell type 1 (Th1) and natural killer cells, interleukin-4 (IL-4) from Th2 cells and Toll-like receptor (TLR) agonists, such as lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria and a widely used standard tool for triggering proinflammatory reactions in myeloid cells
We have shown that microglia undergo a postnatal maturation process, regarding signaling properties of TLRs and including the ability of TLR4 to distinguish between pathogenassociated molecular patterns (PAMPs) ligand variants as to inducible cytokine profiles (Scheffel et al, 2012)
Summary
Reviewed by: Raquel Ferreira, University of Southern California, USA Trevor Owens, University of Southern Denmark, Denmark. We discuss findings and concepts that consider the variety of microglial activities and response options as being based— at least in part—on a diversity of the engaged cells. Whether it is the production of proinflammatory cytokines, clearance of tissue debris, antigen presentation or the ability to sense neurotransmitters, microglial cells present with an unanticipated heterogeneity of their constitutive and inducible features. IL-4 would instruct an “alternative” activation, termed M2, with a distinct profile of induced genes This phenotype assists Th2 type immune responses, exerts anti-inflammatory effects, resolves inflammation and supports tissue repair (Hanisch, 2013b). While reciprocal expression of IL-12 and IL-10 served as a first indicator for M1 versus M2 commitment, and further molecules were identified with more or less biased association, the sets of regulated genes and functions were found way more complex and Frontiers in Cellular Neuroscience www.frontiersin.org
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