NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

“…The surprising role of ROCK1 in limiting inflammatory responses and restraining the assembly of p62 aggregates, furthermore, highlights the challenges of therapeutically targeting this family of kinases, a feat that is being undertaken for several age-related disorders like cardiovascular and, more recently, neurodegenerative diseases including ALS 65,66 . It is indeed likely that the inhibitory roles of ROCK1 that we have identified are not confined to the B cell compartment but may extend to other cell types such as myeloid cells where the combination of PAMPs and heme has recently been shown to drive panoptosis 67 and neurons, which have high bioenergetic demands rendering them more susceptible to environmental insults. This notion is indeed supported by the remarkable concentration of ALS-associated machinery 18 such as TDP-43 and SOD1 in the p62 complexes formed in the absence of ROCK1 suggesting that these aggregates represent a point of convergence for fundamental pathways involved in RNA handling, protein quality control, and oxidative stress.…”

NLRP12‐PANoptosome in haemolytic, infectious and inflammatory diseases

“…These combinations activated robust inflammatory cell death that was dependent on NLRP12 and characterised by activation of specific cell death molecules, including caspase‐1, GSDME, caspase‐8, caspase‐3, caspase‐7 and pMLKL, an activation signature consistent with PANoptosis (Figure 1). 7 While NLRP3 contributed to inflammasome and caspase‐1 activation in this context, it had no effect on cell death or the activation of other PANoptotic molecules 7 . Instead, NLRP12 formed a PANoptosome complex with ASC, caspase‐8 and RIPK3, and potentially other molecules that remain to be characterised, to drive PANoptosis 7 …”

“…7 While NLRP3 contributed to inflammasome and caspase-1 activation in this context, it had no effect on cell death or the activation of other PANoptotic molecules. 7 Instead, NLRP12 formed a PANoptosome complex with ASC, caspase-8 and RIPK3, and potentially other molecules that remain to be characterised, to drive PANoptosis. 7 The formation of the NLRP12-PANoptosome in response to heme plus PAMPs or TNF suggests a critical role for NLRP12-mediated PANoptosis in innate immune responses to conditions where free heme is released, including haemolytic diseases, infections, inflammatory conditions and some cancers.…”

“…7 Instead, NLRP12 formed a PANoptosome complex with ASC, caspase-8 and RIPK3, and potentially other molecules that remain to be characterised, to drive PANoptosis. 7 The formation of the NLRP12-PANoptosome in response to heme plus PAMPs or TNF suggests a critical role for NLRP12-mediated PANoptosis in innate immune responses to conditions where free heme is released, including haemolytic diseases, infections, inflammatory conditions and some cancers. Furthermore, deletion of Nlrp12 significantly reduced pathology and lethality in a murine model of haemolytic disease, 7 providing further physiological relevance and evidence for NLRP12mediated PANoptosis driving inflammation and disease.…”

“…7 The formation of the NLRP12-PANoptosome in response to heme plus PAMPs or TNF suggests a critical role for NLRP12-mediated PANoptosis in innate immune responses to conditions where free heme is released, including haemolytic diseases, infections, inflammatory conditions and some cancers. Furthermore, deletion of Nlrp12 significantly reduced pathology and lethality in a murine model of haemolytic disease, 7 providing further physiological relevance and evidence for NLRP12mediated PANoptosis driving inflammation and disease. Previous research has also linked genetic mutations in NLRP12 to periodic fever syndromes, suggesting there may also be a central role for PANoptosis in these conditions; this requires further study.…”