Cellular inhibitor of apoptosis 2 (cIAP2) restricts neuroinflammation during experimental autoimmune encephalomyelitis

J Neuroinflammation. 2022 Jun 19;19(1):158. doi: 10.1186/s12974-022-02527-6.

Abstract

Background: Immune activation, neuroinflammation, and cell death are the hallmarks of multiple sclerosis (MS), which is an autoimmune demyelinating disease of the central nervous system (CNS). It is well-documented that the cellular inhibitor of apoptosis 2 (cIAP2) is induced by inflammatory stimuli and regulates adaptive and innate immune responses, cell death, and the production of inflammatory mediators. However, the impact of cIAP2 on neuroinflammation associated with MS and disease severity remains unknown.

Methods: We used experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS, to assess the effect of cIAP2 deletion on disease outcomes. We performed a detailed analysis on the histological, cellular, and molecular levels. We generated and examined bone-marrow chimeras to identify the cIAP2-deficient cells that are critical to the disease outcomes.

Results: cIAP2-/- mice exhibited increased EAE severity, increased CD4+ T cell infiltration, enhanced proinflammatory cytokine/chemokine expression, and augmented demyelination. This phenotype was driven by cIAP2-deficient non-hematopoietic cells. cIAP2 protected oligodendrocytes from cell death during EAE by limiting proliferation and activation of brain microglia. This protective role was likely exerted by cIAP2-mediated inhibition of the non-canonical NLRP3/caspase-8-dependent myeloid cell activation during EAE.

Conclusions: Our findings suggest that cIAP2 is needed to modulate neuroinflammation, cell death, and survival during EAE. Significantly, our data demonstrate the critical role of cIAP2 in limiting the activation of microglia during EAE, which could be explored for developing MS therapeutics in the future.

Keywords: Caspase-8; EAE; Microglia; Neuroinflammation; cIAP2.

MeSH terms

  • Animals
  • Baculoviral IAP Repeat-Containing 3 Protein / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism
  • Central Nervous System / pathology
  • Encephalomyelitis, Autoimmune, Experimental* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Multiple Sclerosis* / pathology
  • Neuroinflammatory Diseases

Substances

  • Baculoviral IAP Repeat-Containing 3 Protein