EXPRESS: Sex-dependent roles for RIPK1 in the subacute period of intracerebral hemorrhage in mice.

Receptor-interacting protein kinase-1 (RIPK1) is a serine-threonine kinase that is activated in the brain early after intracerebral hemorrhage (ICH), but its spatial and temporal course in the subacute period is unknown. We used mice deficient in RIPK1 kinase activity to investigate RIPK1 regulation of clinically relevant outcomes in a collagenase ICH model. At 35 days after ICH in wild-type males, RIPK1 was activated (increased in detergent-insoluble fractions) in striatal neurons, endothelium, and astrocytes. In neurons, RIPK1 activation was associated with loss of its regulators TAK1/TBK1, and RIPK1 regulated post-injury neuronal CaMKII𝛼 expression, pathological tau phosphorylation, and inflammasome activation. RIPK1 regulated post-injury gliosis, blood-brain barrier (BBB) damage and cognitive deficits in males. At 35 days after ICH in females, RIPK1 was activated exclusively in neurons but female neurons lacked the biochemical changes seen in males, and RIPK1 did not regulate increased gliosis, BBB damage, or most cognitive deficits in injured females. The studies are the first to describe cell-specific RIPK1 activation in the subacute period of experimental ICH and highlight important sex differences that should inform clinical trials of RIPK1 inhibitors in patients with ICH. Sex differences should be evaluated for RIPK1 in other brain injury models and neurodegenerative disease paradigms.