An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE

Area of Science:

• Neuroimmunology
• Infectious Diseases
• Immunology

Background:

• T-helper 1 cells induce experimental autoimmune encephalomyelitis (EAE) with distinct clinical and pathological features depending on host genetics.
• Myelin oligodendrocyte glycoprotein (MOG)-reactive Th1 cells cause ascending paralysis in wildtype (WT) mice and ataxia in IFNγ receptor (IFNγR)-deficient mice.
• ELR+ CXC chemokines are crucial for atypical EAE (aEAE) but not conventional EAE (cEAE), yet their sources and regulation remain unclear.

Purpose of the Study:

• To elucidate the cellular sources and localization of ELR+ CXC chemokines in the CNS during EAE.
• To investigate the IFNγ-dependent pathways regulating chemokine production in the CNS.
• To understand how these mechanisms dictate the distinct clinical phenotypes of EAE.

Main Methods:

• Immunohistochemistry and in situ hybridization to map inflammatory lesions and chemokine distribution.
• Flow cytometry and quantitative PCR (qPCR) to quantify chemokine and receptor levels on leukocyte subsets.
• In vitro culture of neutrophils and macrophages to assess chemokine production under inflammatory stimuli.

Main Results:

• Neutrophils, monocytes, and microglia are key sources of CXCL2 in the brainstem during aEAE.
• IFNγ suppresses CXCL2 and CXCR2 transcription in myeloid cells and neutrophils, respectively, in WT mice.
• This IFNγ-mediated suppression prevents brainstem infiltration and directs inflammation to the spinal cord in cEAE.

Conclusions:

• An IFNγ-regulated CXCR2/CXCL2 feedback loop in innate immune cells dictates CNS infiltrate localization in Th1-mediated EAE.
• Impaired IFNγ signaling increases CXCL2 production, leading to brainstem inflammation and ataxia.
• IFNγ suppresses myeloid cell CXCL2 and CXCR2, promoting spinal cord inflammation and ascending paralysis, revealing a mechanism for distinct EAE presentations.