Systemic Inflammation Modulates Fc Receptor Expression on Microglia during Chronic Neurodegeneration

Abstract

Chronic neurodegeneration is a major worldwide health problem, and it has been suggested that systemic inflammation can accelerate the onset and progression of clinical symptoms. A possible explanation is that systemic inflammation “switches” the phenotype of microglia from a relatively benign to a highly aggressive and tissue-damaging phenotype. The current study investigated the molecular mechanism underlying this microglia phenotype “switching.” We show in mice with chronic neurodegeneration (ME7 prion model) that there is increased expression of receptors that have a key role in macrophage activation and associated signaling pathways, including TREM-2, Siglec-F, CD200R, and FcγRs. Systemic inflammation induced by LPS further increased protein levels of the activating FcγRIII and FcγRIV, but not of other microglial receptors, including the inhibitory FcγRII. In addition to these changes in receptor expression, IgG levels in the brain parenchyma were increased during chronic neurodegeneration, and these IgG levels further increased after systemic inflammation. γ-Chain–deficient mice show modified proinflammatory cytokine expression in the brain after systemic inflammation. We conclude that systemic inflammation during chronic neurodegeneration increases the expression levels of activating FcγR on microglia and thereby lowers the signaling threshold for Ab-mediated cell activation. At the same time, IgG influx into the brain could provide a cross-linking ligand resulting in excessive microglia activation that is detrimental to neurons already under threat by misfolded protein.

The Evolving Biology of Microglia in Alzheimer's Disease

“…While there are numerous siglecs involved in the phenotypic regulation of myeloid cells specifically in AD [112,113], the siglec CD33 has been the best characterized. Upon binding its sialic acid ligand [114], CD33 was shown to promote downregulation of myeloid cell activation in the periphery [115].…”

Innate Inflammation in Parkinson's Disease

“…The density of the ligands expressed by neurons will be reduced during the progression of a neurodegenerative disease and will thus influence the level of inhibitory tone on the microglia. During neurodegeneration, there may also be a shift toward the expression of ITAM (immunoreceptor tyrosine-based activating motif ) -bearing receptors such as several of the Fc receptors (Lunnon et al 2011). † The changes in expression of neuronal ligands and the receptors that regulate the microglia phenotype in the progression of PD remain to be investigated.…”

“…In brains with ongoing chronic neurodegeneration, there is a growing body of evidence to show that the microglia are not only increased in number and have an activated phenotype, but appear to be "primed" by the ongoing pathology such that systemic inflammation leads to an exaggerated synthesis of pro-inflammatory cytokines Cunningham et al 2009;Field et al 2010). The switch in the microglia phenotype during systemic inflammation has been described in pre-clinical models of both acute (Palin et al 2008) and chronic (Cunningham et al 2005;Lunnon et al 2011) neurodegeneration. Studies in animal models show that systemic inflammation can lead to exaggerated acute symptoms of brain disease, accelerate disease progression (Cunningham et al 2005, and increase neuronal loss (Cunningham et al 2005;Pott Godoy et al 2008).…”

The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis

“…This activation is characterized by increased expression of the anti-inflammatory cytokines TGF-b and PGE 2 , signalling receptors including Trem2, SiglecF, CD200R, and Fcg receptors, and the development of a highly branched morphology (Lunnon et al, 2011). These are characteristic of an anti-inflammatory profile such as that exhibited by macrophages following their engulfment of apoptotic cells (Fadok et al, 1998).…”

“…exposure to pathogen-associated molecular patterns such as bacterial LPS (Combrinck et al, 2002;Cunningham et al, 2005;Lunnon et al, 2011). These changes to microglial status acutely exaggerate the cognitive decline, impair motor coordination and accelerate CNS prion disease progression (Combrinck et al, 2002;Cunningham et al, 2005Cunningham et al, , 2009).…”