Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System

Abstract

Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14++CD16− classical monocytes, CD14++CD16+ intermediate monocytes, and CD14+CD16++ non-classical monocytes. Whereas CD16− classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16+ monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16+ monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16+ monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16+ to CD16− CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16+ monocytes were detected in a perivascular location within active MS lesions, and CD16+ monocytes facilitated CD4+ T cell trafficking in a blood–brain barrier model. Our findings support an important role of CD16+ monocytes in the steady-state immune surveillance of the CNS and suggest that CD16+ monocytes shift to sites of inflammation and contribute to the breakdown of the blood–brain barrier in CNS autoimmune diseases.

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

“…The second differentiating cell type was the non-classical monocyte (CD16+); this was significantly decreased in ODC compared with HC but not in CIS. This finding is supported by recent publications analysing CD16+ monocytes and their gene expression in peripheral blood and the CSF of people with MS [16,17]. CD16+ monocytes from MS patients tend to have increased surface expression of activation markers and respond more robustly with inflammatory cytokine production to in vitro stimulation compared with cells from healthy controls [18,19].…”

Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis

“…Previous reports of surface marker expression on inflammatory monocyte populations have been mixed due to the relative recent distinction between intermediate and nonclassical monocytes, but levels of CD40 and CD192 expression have generally been reported as higher in MS compared to controls, notably in treated patients . Also, a recent study analyzed monocyte subsets in the peripheral blood and CSF in a cohort of newly diagnosed patients with MS or CIS and found functionally competent but reduced numbers of intermediate and nonclassical monocytes in treatment‐naïve patients, and increased numbers in treated patients compared to healthy controls. This apparent discrepancy is most likely due to the composition of the different patient cohorts, and reflects an important point of disease heterogeneity.…”

“…The influence of the homeostasis between pro‐ and anti‐inflammatory monocyte populations on the replenishing macrophages at the site of action is not entirely clear. In the case of MS, this site is notably the CNS …”

Complement 3a receptor in dorsal horn microglia mediates pronociceptive neuropeptide signaling

“…The present study makes the intriguing and novel observation that C3aR1 is expressed in meningeal/subarachnoid monocytes. It is well documented that monocytes can be found in mouse meninges and human cerebrospinal fluid, and that their number increases in pathological states such as multiple sclerosis (Chinnery, Ruitenberg, & McMenamin, ; Polfliet et al, ; Waschbisch et al, ). Thus, we suggest that C3aR1 is well‐positioned to respond to complement pathway activation within the cerebrospinal fluid (e.g., in response to pathogens).…”