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Rationale for IL-1β-targeted therapy to minimize hypoxic-ischemic encephalopathy

Journal of Perinatology volume 29, pages 785–787 (2009)Cite this article

The purpose of this commentary is to propose the involvement of a proinflammatory immune mechanism during intrapartum hypoxia–ischemia that may contribute to neonatal hypoxic-ischemic encephalopathy (HIE). The following hypothesis posits that an intrapartum hypoxic-ischemic event can induce prolonged intracellular acidosis with associated tissue breakdown and cause formation of intra- and extracellular danger-associated molecular patterns (DAMPs), that is, extracellular ATP, uric acid/urate and calcium pyrophosphate crystals, and intracellular hypokalemia, which can stimulate the cryopyrin inflammasome (that is, NACHT domain leucine rich repeat and PYD (NALP)-3 inflammasome) to secrete interleukin (IL)-1β with subsequent neutrophilic inflammation associated with HIE.1

As the NALP-3 inflammasome may be involved, the following is a short review of salient investigations involving this innate multiprotein cytoplasmic structure. Hoffman et al.2 identified the cryopyrin-encoding gene on chromosome 1q44 by investigating Familial Cold Autoinflammatory Syndrome, a rare autoinflammatory, autosomal-dominant syndrome characterized by cold induction of IL-1β secretion that causes fever, neutrophilic leukocytosis and neutrophil leukocyte-infiltrated dermatosis.2, 3 The cryopyrin gene discovery led to recognition of the NALP-3 inflammasome, which is comprised of a cytoplasmic macromolecular protein complex containing cryopyrin and other adaptor proteins.4 Two other rare and seemingly unrelated autosomal-dominant periodic fever syndromes (that is, Muckle–Wells and Neonatal Onset Multisystem Inflammatory Disease, NOMID) with dysregulated elevated 1L-1 β production were found to have mutations on the same gene. All three autoinflammatory hereditary syndromes, referred to as cryopyrin-associated periodic syndromes (CAPSs), are exceptionally responsive to IL-1β-targeted therapy (IL-1β TT), which provided unequivocal evidence for IL-1β mediation in human disorders with dominant neutrophilic inflammation.5, 6 Subsequently, investigators recognized that DAMPs can stimulate the NALP-3 inflammasome to secrete IL-1β,7 which in turn is capable of inducing a cascade of proinflammatory molecular events (that is, upregulation of vascular intercellular adhesion molecule (ICAM), IL-6 release, increased neutrophil and monocyte chemokines, and IL-17 A secretion), and thereby cause profound neutrophilic inflammation.1 Moreover, there is now convincing evidence to suggest that blocking IL-1β can significantly diminish neutrophilic inflammation in many conditions, that is, the three CAPSs5, 6, 8 and other IL-1β-mediated neutrophilic inflammatory disorders, such as recalcitrant gout,9 Still's juvenile arthritis and Schnitzler syndrome.1 Even recently described mutational syndromes with deficiency of IL-1β receptor antagonists exhibit manifestations of unopposed IL-1β-mediated neutrophilic pustulosis and osteomyelitis, which are also very responsive to IL-1β-targeted therapy.10 The excellent response to IL-1β-targeted therapy provides the basis for their consideration in treating disorders with dominant neutrophilic inflammation associated with IL-1β secretion, such as in ischemia-reperfusion syndromes, of which HIE is an example.

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  1. Department of Pediatrics, Allergy and Clinical Immunology, University of Colorado Health Sciences Center, Denver, USA

    A A Wanderer

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Wanderer, A. Rationale for IL-1β-targeted therapy to minimize hypoxic-ischemic encephalopathy. J Perinatol 29, 785–787 (2009). https://doi.org/10.1038/jp.2009.114

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