ICAM1+ neutrophils promote chronic inflammation via ASPRV1 in B cell–dependent autoimmune encephalomyelitis
Ryder F. Whittaker Hawkins, Alexandre Patenaude, Aline Dumas, Rajiv Jain, Yodit Tesfagiorgis, Steven Kerfoot, Takeshi Matsui, Matthias Gunzer, Patrice E. Poubelle, Catherine Larochelle, Martin Pelletier, Luc Vallières
Ryder F. Whittaker Hawkins, Alexandre Patenaude, Aline Dumas, Rajiv Jain, Yodit Tesfagiorgis, Steven Kerfoot, Takeshi Matsui, Matthias Gunzer, Patrice E. Poubelle, Catherine Larochelle, Martin Pelletier, Luc Vallières
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Research Article Neuroscience

ICAM1+ neutrophils promote chronic inflammation via ASPRV1 in B cell–dependent autoimmune encephalomyelitis

Abstract

Neutrophils contribute to demyelinating autoimmune diseases, yet their phenotype and functions have been elusive to date. Here, we demonstrate that ICAM1 surface expression distinguishes extra- from intravascular neutrophils in the mouse CNS during experimental autoimmune encephalomyelitis (EAE). Transcriptomic analysis of these 2 subpopulations indicated that neutrophils, once extravasated, acquire macrophage-like properties, including the potential for immunostimulation and MHC class II–mediated antigen presentation. In corroboration, super-resolution (3D stimulated emission-depletion [STED]) microscopy revealed neutrophils forming synapses with T and B cells in situ. Further, neutrophils specifically express the aspartic retroviral-like protease ASPRV1, which increases in the CNS during EAE and severe cases of multiple sclerosis. Without ASPRV1, mice immunized with a new B cell–dependent myelin antigen (but not with the traditional myelin oligodendrocyte glycoprotein peptide) develop a chronic phase of EAE that is less severe and even completely fades in many individuals. Therefore, ICAM1+ macrophage–like neutrophils can play both shared and nonredundant roles in autoimmune demyelination, among them perpetuating inflammation via ASPRV1.

Authors

Ryder F. Whittaker Hawkins, Alexandre Patenaude, Aline Dumas, Rajiv Jain, Yodit Tesfagiorgis, Steven Kerfoot, Takeshi Matsui, Matthias Gunzer, Patrice E. Poubelle, Catherine Larochelle, Martin Pelletier, Luc Vallières

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Figure 4

ICAM1+ neutrophils have a distinct transcriptional profile suggestive of a capacity for immunomodulation and antigen presentation.

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ICAM1+ neutrophils have a distinct transcriptional profile suggestive of...
(A) Heat map of mRNAs differentially expressed in ICAM1+ and ICAM1– neutrophils (N+, N–) compared with each other or with CD11b+CD11c–Ly6G– macrophages (Mc) and CD11b+CD11c+Ly6G– DC. These cells were simultaneously purified from the spinal cord of EAE mice by FACS and analyzed by DNA microarray. The hierarchical clustering dendrogram shows the degree of similarity among the samples (biological duplicates). The color scale indicates the hybridization signal intensity. The criteria used for comparison were as follows: fold change ≥ 3; hybridization signal ≥ 200; 2-tailed Student’s t test, P ≤ 0.05. See Supplemental Tables 1–4 for data sets. (B) Frequency distribution, according to biological function, of the 343 mRNAs identified as enriched in ICAM1+ neutrophils. (C) Fold difference in the hybridization signals for mRNAs of 3 selected categories (blue text in B), as compared between ICAM1+ and ICAM1– neutrophils. (D) Fold difference in the hybridization signals for neutrophil-specific mRNAs, as compared between neutrophils (ICAM1+ and ICAM1–) and macrophages. (E) Signaling proteins expressed (light blue) or upregulated (dark blue) in ICAM1+ neutrophils, supporting the concept that these cells acquire immunostimulatory capacities. (F) Schematic of the MHCII pathway showing that all of the proteins are upregulated (dark blue) in ICAM1+ neutrophils, suggesting the acquisition of antigen-presenting capacity. Color legend as in E. MIIC, MHCII compartment.