. 2022 Apr 29;11(9):1495. doi: 10.3390/cells11091495

Table 2.

Totality of cell death in disease phenotypes.

Model	Pathology	Pyroptosis		Apoptosis		Necroptosis		PANoptosis
Model	Pathology	Genotype	Disease?	Genotype	Disease?	Genotype	Disease?	Genotype	Disease?
**Pstpip2^cmo** [16,18,140,141]	Osteomyelitis	Nlrp3 ^−/−	✔	Casp8 ^−/− Ripk3 ^{−/− a}	✔	Ripk3 ^−/−	✔	Nlrp3 ^−/− Casp8 ^−/− Ripk3 ^−/−	X
**Pstpip2^cmo** [16,18,140,141]	Osteomyelitis	Casp1 ^−/−	✔	Casp8 ^−/− Ripk3 ^{−/− a}	✔	Ripk3 ^−/−	✔	Casp1 ^−/− Casp8 ^−/− Ripk3 ^−/−	X
**Sharpin^cpdm** [142,143,144,145,146]	Dermatitis	Nlrp3 ^−/−	D	Bid ^−/−	D	Mlkl ^−/−	D	Ripk3 ^−/− Fadd ^E-KO	X
		Nlrp3 ^−/−	D			Ripk3 ^−/−	D	Ripk3 ^−/− Tradd ^E-KO	X
		Casp1/11 ^−/−	D			Ripk1 ^K45A	X	Casp8 ^−/− Ripk3 ^−/−	X ^b
**Ptpn6^spin** [147,148]	Dermatosis	Nlrp3 ^−/−	✔	Casp8 ^−/− Ripk3 ^{−/− a}	✔	Ripk3 ^−/−	✔	Casp8 ^−/− Ripk1 ^−/− Ripk3 ^−/−	X
		Nlrp3 ^−/−	✔			Mlkl ^−/−	✔
		Casp1 ^−/−	✔			Ripk1 ^K45A	✔
**Hoildeficiency** [149]	Embryonic lethality			Casp8 ^−/−	✔	Ripk3 ^−/−	D	Casp8 ^−/− Mlkl ^−/−	D
				Casp8 ^−/− Ripk3 ^{−/− a}	D ^c	Mlkl ^−/−	D	Casp8 ^−/− Ripk1^−/− Ripk3 ^−/−	X
				Casp8 ^−/− Ripk3 ^{−/− a}	D ^c	Ripk1 ^K45A	D	Casp8 ^−/− Ripk1^−/− Ripk3 ^−/−	X
Caspase-8 deficiency [62,81,82,83,84,131]	Embryonic lethality			Casp8 ^−/−	✔	Ripk1^D ¹³⁸ ^N	D	Casp8 ^−/− Ripk3 ^−/−	X
Caspase-8 deficiency [62,81,82,83,84,131]	Embryonic lethality			Casp8 ^−/−	✔	Ripk1^D ¹³⁸ ^N	D	Casp8 ^−/− Mlkl ^−/−	X
**Casp8^C362A** [130]	Embryonic lethality	Nlrp3 ^−/− Mlkl ^−/−	✔	Fadd ^−/− Mlkl ^−/−	D	Mlkl ^−/−	✔	Casp1/11 ^−/− Ripk3 ^−/−	X
		Casp1 ^−/− Mlkl ^−/−	✔			Mlkl ^−/−	✔	Casp1/11 ^−/− Ripk3 ^−/−	X
		Casp11 ^−/− Mlkl ^−/−	D			Ripk3 ^−/−	D	Casp1/11 ^−/− Mlkl ^−/−	X
		Asc ^−/− Mlkl ^−/−	D			Ripk3 ^−/−	D	Casp1/11 ^−/− Mlkl ^−/−	X
LPS shock [2,150]	Lethality	Asc ^−/−	✔			Ripk3 ^−/−	✔	Casp8 ^−/− Ripk3 ^−/−	X
		Asc ^−/−	✔					Casp8 ^−/− Ripk3 ^K51A	X
		Casp11 ^−/−	D					Casp8 ^−/− Ripk3 ^−/− Ripk1 ^−/−	X
TNF + IFN-γshock [2]	Lethality					Ripk3 ^−/−	✔	Casp8 ^−/− Ripk3 ^−/−	X
FlaTox injection [151,152]	Hypothermia	Nlc4 ^−/−	X	Casp8 ^−/− Ripk3 ^{−/− a}	✔	Ripk3 ^−/−	✔	Casp1 ^−/− Ripk3 ^−/−	D
		Asc ^−/−	✔					Casp1 ^−/− Casp8 ^−/− Ripk3 ^−/−	X
		Casp1 ^−/−	D					Asc ^−/− Casp8 ^−/− Ripk3 ^−/−	X
		Casp1/11 ^−/−	D
		Gsdmd ^−/−	D

^aCasp8^−/−Ripk3^−/− genotype is considered as an apoptosis deletion only when the phenotype is the same as the Ripk3^−/− genotype, showing that the added deletion of apoptotic caspase-8 does not affect the phenotype. ^b Sharpin^cpdmCasp8^−/−Ripk3^−/− mice could be born but did not survive to weaning. ^c Hoil^−/−Casp8^−/−Ripk3^−/− mice succumb at late gestation through a process that appears to be independent of cell death, while Hoil^−/−Casp8^+/−Ripk3^−/− mice undergo cell death-induced loss of yolk sac vascularization to contribute to lethality. Disease phenotypes in mouse models are associated with many different cell death molecules. Deletion of specific combinations can alleviate disease. The totality of biological effects in these studies cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone, leading to the conceptualization of PANoptosis. For genotypes representing a disruption in each programmed cell death pathway, the presence or absence of disease (Disease?) is denoted for each. ✔, disease or lethality occurs at levels similar to those seen in wild-type animals; D, decreased disease or lethality as compared with wild-type; X, no disease or lethality (rescued).