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. 2016 Jun 6;13(1):138.
doi: 10.1186/s12974-016-0605-8.

Expression of IL-1β in rhesus EAE and MS lesions is mainly induced in the CNS itself

Saskia Maria Burm  1 , Laura Anna Norma Peferoen  2 , Ella Alwine Zuiderwijk-Sick  1 , Krista Geraldine Haanstra  3 , Bert Adriaan 't Hart  3 , Paul van der Valk  2 , Sandra Amor  2 , Jan Bauer  4 , Jeffrey John Bajramovic  5
Affiliations

Expression of IL-1β in rhesus EAE and MS lesions is mainly induced in the CNS itself

Saskia Maria Burm et al. J Neuroinflammation. .

Abstract

Background: Interleukin (IL)-1β is a pro-inflammatory cytokine that plays a role in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Yet, detailed studies on IL-1β expression in different stages of MS lesion development and a comparison of IL-1β expression in MS and EAE are lacking.

Methods: Here, we performed an extensive characterization of IL-1β expression in brain tissue of MS patients, which included different MS lesion types, and in brain tissue of rhesus macaques with EAE.

Results: In rhesus EAE brain tissue, we observed prominent IL-1β staining in MHC class II(+) cells within perivascular infiltrates and at the edges of large demyelinating lesions. Surprisingly, staining was localized to resident microglia or differentiated macrophages rather than to infiltrating monocytes, suggesting that IL-1β expression is induced within the central nervous system (CNS). By contrast, IL-1β staining in MS brain tissue was much less pronounced. Staining was found in the parenchyma of active and chronic active MS lesions and in nodules of MHC class II(+) microglia in otherwise normal appearing white matter. IL-1β expression was detected in a minority of the nodules only, which could not be distinguished by the expression of pro- and anti-inflammatory markers. These nodules were exclusively found in MS, and it remains to be determined whether IL-1β(+) nodules are destined to progress into active lesions or whether they merely reflect a transient response to cellular stress.

Conclusions: Although the exact localization and relative intensity of IL-1β expression in EAE and MS is different, the staining pattern in both neuroinflammatory disorders is most consistent with the idea that the expression of IL-1β during lesion development is induced in the tissue rather than in the periphery.

Keywords: Experimental autoimmune encephalomyelitis; IL-1β; Inflammasome; Microglia; Multiple sclerosis; Preactive lesion.

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Figures

Fig. 1
Fig. 1
IL-1β expression in brain tissue of rhesus macaques with EAE induced by rhMOG in IFA. Brain lesions were characterized based on the extent of myelin (PLP in brown, left panels) damage and activation of innate immune cells (MHC class II in brown, middle panels). In small perivascular lesions without signs of demyelination (a), IL-1β staining (in brown, right panels) was mainly localized in MHC class II+ cells at the edge of the lesion. In mid-sized MHC class II+ lesions with clear signs of demyelination (b), IL-1β staining was more pronounced. In large fulminating lesions with extensive demyelination and infiltration of MHC class II+ cells (c), IL-1β staining was less pronounced compared to the mid-sized lesions and observed at the edge of the demyelinated area. Double labeling of perivascular lesions for IL-1β (in green) and Iba-1 or MRP14 (in red) demonstrated that all IL-1β+ cells were Iba-1+ (d), whereas all IL-1β+ cells were MRP14− or MRP14low (e). Original magnifications ×10, scale bar represents 200 μm, insets ×100. Nuclei were counterstained with hematoxylin (blue)
Fig. 2
Fig. 2
IL-1β expression in brain tissue of rhesus macaques with EAE induced by rhMOG in CFA. Brain lesions were characterized based on the extent of myelin (PLP in brown, left panels) damage and activation of innate immune cells (MHC class II in brown, middle panels). In small perivascular lesions without signs of demyelination (a), IL-1β staining (in brown, right panels) was mainly localized in MHC class II+ cells at the edge of the lesion. In large fulminating lesions with extensive demyelination and infiltration of MHC class II+ cells (b), IL-1β staining was more pronounced and mainly observed at the edges of the demyelinated area. Double labeling of perivascular lesions for IL-1β (in green) and Iba-1 or MRP14 (in red) demonstrated that all IL-1β+ cells were Iba-1+ (c), whereas all IL-1β+ cells were MRP14− or MRP14low (d). Original magnifications ×10, scale bar represents 200 μm, insets ×100
Fig. 3
Fig. 3
IL-1β expression in different types of MS lesions. MS lesions in paraffin-embedded brain tissue sections were characterized based on the extent of myelin (PLP in brown, left panels) damage and activation of innate immune cells (MHC class II in brown, middle panels). Active MS lesions were classified as areas with ongoing demyelination and activation of MHC class II+ innate immune cells (a). Chronic active lesions were classified by the presence of a completely demyelinated (PLP−) center surrounded by a rim of MHC class II+ cells (b). Inactive lesions were classified by the presence of demyelinated areas where the immune response has resided (c). We did not detect IL-1β (in brown, right panels) in active, chronic active, and inactive MS lesions in paraffin-embedded tissue sections (a–c). In addition, we observed MHC class II+ microglia nodules in otherwise NAWM (d) in which IL-1β was expressed. Double labeling of these microglia nodules for IL-1β (in red) and Iba-1 (in green) implicated that all IL-1β+ cells were Iba-1+ (e). Original magnifications ×4, insets ×100 (a–d), scale bar represents 500 μm (a–d) or 10 μm (e). Nuclei were counterstained with hematoxylin (blue; a–d)
Fig. 4
Fig. 4
IL-1β expression in different types of MS lesions. MS lesions in frozen brain tissue sections were characterized based on the extent of myelin (PLP in brown, left panels) damage and activation of innate immune cells (MHC class II in brown, middle panels). Active MS lesions were classified as areas with ongoing demyelination and activation of MHC class II+ innate immune cells (a). IL-1β expression (in brown, right panels) was mainly observed in ramified MHC class II+ cells in the parenchyma, which were mainly localized at the edges of active lesions. Chronic active lesions were classified by the presence of a completely demyelinated (PLP−) center surrounded by a rim of MHC class II+ cells (b). IL-1β expression was observed in MHC class II+ cells in the rim of the lesion. Again, we observed MHC class II+ microglia nodules in otherwise NAWM (c) in which IL-1β was expressed. Original magnifications ×10, insets ×40 (a–c), scale bar represents 200 μm
Fig. 5
Fig. 5
Activation status of IL-1β+ cells in microglia nodules. Microglia nodules were classified as clusters of MHC class II+ cells in otherwise NAWM. These clusters of activated microglia were double stained for IL-1β (in brown) and cell surface markers associated with pro-inflammatory or anti-inflammatory cellular phenotypes (in red). IL-1β staining colocalized with MHC class II (a) and cell surface markers CD74 (b) and CD40 (c) as well as with CD200R (d). In most microglia nodules, IL-1β staining also colocalized with CCL22 (e), although some microglia nodules contained IL-1β+/CCL22− cells. IL-1β+ microglia did not express MR (f). Original magnifications: ×40, scale bar represents 50 μm. Nuclei were counterstained with hematoxylin (blue)
Fig. 6
Fig. 6
IL-1β expression in perivascular infiltrates in active MS lesions. Within the active lesions of two patients, we observed perivascular infiltrates in areas with ongoing demyelination (PLP, in brown; a). These perivascular cells were strongly MHC class II+ (in brown; b). We observed IL-1β expression (in brown) in cells associated with these perivascular infiltrates, mainly at the edges of the infiltrate and the parenchyma (c). These cells were double stained for IL-1β (in brown) and cell surface markers associated with pro-inflammatory or anti-inflammatory cellular phenotypes (in red). IL-1β staining colocalized with MHC class II (d) and CD74, although we also observed multiple IL-1β+/CD74− cells (e). Furthermore, IL-1β staining colocalized with CD40 (f), CD200R (g), and CCL22, although we also observed some IL-1β+/CCL22− cells (h). IL-1β and MR staining were both observed in the same perivascular infiltrates, but all IL-1β+ cells were MR− (i). In addition, within one active lesion, we observed MHC class II+ cells (in red) with a foamy appearance (j). These MHC class II+ foamy cells did not express detectable levels of IL-1β. In addition, we observed some IL-1β staining (in brown) in reactive astrocytes in the same active lesion (k). Original magnifications ×40, scale bar represents 50 μm. Nuclei were counterstained with hematoxylin (blue)
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