Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone‐induced demyelination

Abstract

Microglia are resident immune cells in the CNS, strategically positioned to clear dead cells and debris, and orchestrate CNS inflammation and immune defense. In steady state, these macrophages lack MHC class II (MHCII) expression, but microglia activation can be associated with MHCII induction. Whether microglial MHCII serves antigen presentation for critical local T-cell restimulation in CNS auto-immune disorders or modulates microglial signaling output remains under debate. To probe for such scenarios, we generated mice harboring an MHCII deficiency in microglia, but not peripheral myeloid cells. Using the CX CR1 -based approach we report that microglial antigen presentation is obsolete for the establishment of EAE, with disease onset, progression, and severity unaltered in mutant mice. Antigen presentation-independent roles of microglial MHCII were explored using a demyelination model induced by the copper chelator cuprizone. Absence of microglial I-A did not affect the extent of these chemically induced white matter alterations, nor did it affect microglial proliferation or gene expression associated with locally restricted de- and remyelination.

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…Using radiation bone marrow chimeric animals and disease induction with MHC mismatched donor T-cells, it was shown that antigen presentation on CNS resident microglia and monocytes is not necessary for disease induction (Hickey & Kimura, 1988). This has recently been confirmed using transgenic mouse lines with specific deletion of MHC Class II antigens in microglia (Wolf et al, 2018).…”

“…Using radiation bone marrow chimeric animals and disease induction with MHC mismatched donor T‐cells, it was shown that antigen presentation on CNS resident microglia and monocytes is not necessary for disease induction (Hickey & Kimura, ). This has recently been confirmed using transgenic mouse lines with specific deletion of MHC Class II antigens in microglia (Wolf et al, ). Brain inflammation is induced by the antigen‐specific interaction of T‐cells with meningeal and perivascular antigen presenting cells (Bartolomäus et al, ; Flügel et al, ; Mues et al, ).…”

“… Note : The table compares the key features of inflammatory lesions in the central nervous system mediated by different T‐cell populations, B‐cells, and innate immunity in rodent models and humans, also describing the reaction patterns of microglia/macrophages and astrocytes. References 1: Ajami et al (), 2: Ben‐Nun, Wekerle, and Cohen (), Lassmann et al (), 4: Wolf et al (), 5: Blaabjerg et al (). 6: Mayo et al (), 7: Basso et al (). 8: Bradl and Lassmann (), 9: Linington, Bradl, Lassmann, Brunner, and Vass (), 10: Misu et al (), 11: Pohl et al, , 12: Storch et al (). 13: Bien et al (), 14: Cabarrocas, Bauer, Piaggio, Liblau, and Lassmann (), 15: Dauvilliers et al (), 16: Ji, Perchellet, and Goverman (), 17: Laukoter et al (), 18: Na et al (), 19: Saxena et al (), 20: Steinbach et al (), 21: Tröscher et al (). 22: Machado‐Santos et al (), 23: van Nierop et al (), 24: Zrzavy et al (). 25: Felts et al (), 26: Marik, Felts, Bauer, Lassmann, and Smith (), 27: Nau and Brück (2002). …”

“…1: Ajami et al (), 2: Ben‐Nun, Wekerle, and Cohen (), Lassmann et al (), 4: Wolf et al (), 5: Blaabjerg et al ().…”

Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis

“…Consistent with this, time-course studies in EAE mice showed that the appearance of inflammatory T cells in the CNS is consistent with the activation of CD11b + microglia (Murphy et al, 2010). However, specific deletion of MHCII in microglia does not affect disease progression, suggesting that microglia are not important in reactivating efficient T cells in the CNS (Wolf et al, 2018). Microglia also secrete a series of pro-inflammatory cytokines such as IL-18, IL-6, and IL-1b and chemokines like CCL2 and CCL5 to aggravate both MS and EAE (Merson et al, 2010; Jiang et al, 2014).…”