The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus

Abstract

Inflammation is an integral part of the body's physiological repair mechanism, unless it remains unresolved and becomes pathological, as evident in the progressive nature of neurodegeneration. Based on studies from outside the central nervous system (CNS), it is now understood that the resolution of inflammation is an active process, which is dependent on well-orchestrated innate and adaptive immune responses. Due to the immunologically privileged status of the CNS, such resolution mechanism has been mostly ignored. Here, we discuss resolution of neuroinflammation as a process that depends on a network of immune cells operating in a tightly regulated sequence, involving the brain's choroid plexus (CP), a unique neuro-immunological interface, positioned to integrate signals it receives from the CNS parenchyma with signals coming from circulating immune cells, and to function as an on-alert gate for selective recruitment of inflammation-resolving leukocytes to the inflamed CNS parenchyma. Finally, we propose that functional dysregulation of the CP reflects a common underlying mechanism in the pathophysiology of neurodegenerative diseases, and can thus serve as a potential novel target for therapy.

Figure 1

Under neuroinflammatory situations, either acute (upper part) or chronic (bottom part), CNS parenchymal damage (black line) leads to glial cell activation and to local inflammatory response (red line). In response to acute CNS damage, circulating leukocytes are recruited to the CNS (blue line) and participate in the resolution of the innate inflammatory response. When such a response is not resolved it may lead to chronic neuroinflammation, associated with escalating toxicity and neuronal death, which is the case in chronic neurodegenerative diseases; the lack of resolution reflects insufficient recruitment of systemic inflammation-resolving immune cells to the CNS.

Figure 2

Notably, the distinct peripheral immunological states found in the different neurodegenerative conditions emphasize that opposite immunomodulatory approaches might be needed for resolution of local neuroinflammation under autoimmune inflammatory disease (blue line and dashed blue line) versus chronic neurodegenerative disease (red line and dashed red line).

Figure 3

(1) In the steady state, astrocytes and microglia serve as sentinels of tissue homeostasis, providing the neural parenchyma with a supportive neurotrophic environment. (2) Following CNS insult, dying cells and accumulation of cellular debris locally activate resting microglia and astrocytes. Activated microglia phagocytose cellular debris while concurrently secreting toxic compounds, including pro-inflammatory cytokines (such as IL-1β, TNF-α and IL-6) and reactive oxygen and nitrogen species (ROS, NOS). (3) Parenchymal-derived signals (e.g., TNF-α) reach the choroid plexus (CP) through the cerebrospinal fluid (CSF) and are sensed by cytokine receptors and Toll-like receptors (TLRs) expressed by the CP epithelium. (4) These signals, together with IFN-γ from CP stromal Th1 cells, initiate a cellular trafficking cascade for T cells and monocytes entering the CNS. This cascade includes the upregulation of integrin receptors (e.g. ICAM-1), chemokines (e.g. CXCL10) and surface enzymes (e.g. CD73) by the CP epithelium, which enables selective recruitment of leukocytes to the CNS. (5) Entry through the CP-CSF serves an educative role in skewing infiltrating immune cells towards an anti-inflammatory/suppressor phenotype. (6) Along the repair process, monocyte-derived macrophages and regulatory T cells (Tregs) are recruited to the inflamed CNS parenchyma and suppress the inflammatory response by the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. (7) In chronic neurodegenerative diseases, circulating immune suppressor cells [such as Tregs and myeloid-derived suppressor cells (MDSCs)] maintain peripheral immune suppression and inhibit immune cell trafficking to the CNS. (8) Lacking the support of circulating inflammation-resolving leukocytes, dying cells, cellular debris and protein aggregates locally activate astrocytes and microglia in an escalating vicious cycle of local toxicity; neurons residing in this inflammatory microenvironment degenerate via apoptotic mechanisms.

Figure 4

(1) Dating back to the 19^th century, with the first observations of Paul Ehrlich regarding the anatomical separation of the CNS (Ehrlich, 1885), and continuing for the first half of the 20^th century by the works of Shirai (1921) and Medawar (1948), the CNS was traditionally viewed as an immune privileged site. (2) At the time, according to the ‘clonal selection theory’ of Burnet (Burnet, 1959) and Lederberg (Lederberg, 1959), autoimmune T cells were considered to have only pathological roles. (3) Over the years, however, the presence of tissue-specific immune cells in healthy individuals raised the question of their nature and challenged the clonal deletion theory (Jerne, ; Cohen, ; Matzinger, 1994). (4) Studies showing that peripheral immunological activation can elevate T cell numbers in the CNS were the first to suggest a physiological immune surveillance mechanism (Hickey & Kimura, ; Hickey et al, 1991). Immune surveillance was found to constitutively take place at the ‘borders’ of the CNS – the CSF, the meningeal spaces, and the choroid plexus (Carrithers et al, ; Kivisakk et al, ; Ransohoff et al, 2003) (5) In the late 1990s, and early 2000s, a physiological role was attributed to autoimmune T cells in CNS repair (Moalem et al, ; Hauben et al, ; Wolf et al, 2002) and maintenance (Kipnis et al, ; Ziv et al, 2006). (6) Our model suggests that CNS-specific CD4⁺ T cells constitutively reside at the brain's choroid plexus, controlling brain homeostasis from afar (Baruch & Schwartz, ; Baruch et al, 2013). This neuro-immunological interface serves as a tightly regulated entry gate into the CNS for immune surveillance by circulating leukocytes under physiological conditions, and for repair following CNS damage (Kunis et al, ; Shechter et al, 2013b).