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By Jamshed Arslan, Pharm. D., PhD.
Death is perhaps inevitable. Cell death can be programed and immunologically silent (apoptosis), unprogrammed and inflammatory (necrosis), or both programmed and inflammatory (necroptosis). Ligands like TNF, FasL and TRAIL can trigger both apoptosis and necroptosis. Just like necrosis, the necroptotic cell swells and bursts, releasing danger-associated molecular patterns (DAMPs). Innate immune system detects DAMPs as a signature of danger and triggers inflammatory response.1,2,3
Necroptosis is a programmed necrosis triggered by the activation of receptor interacting protein (RIP) kinase-1 (RIPK1) and kinase-3 (RIPK3). The RIP homotypic interaction motif (RHIM) of both kinases interact to form a cytosolic complex called necrosome in which RIPK1 and RIPK3 phosphorylate each other. This, in turn, recruits and activates a pseudokinase MLKL, resulting in necroptosis. RIPK1, RIPK3 and MLKL are all targets of intervention against necroptosis-mediated inflammation and pathology.1,2,3
View Our Apoptosis, Necroptosis, and Autophagy Pathway Poster
Immunocytochemical staining showing RIPK3/RIP3 expression in immersion fixed SK-BR-3 human breast cancer cell line (left) versus HepG2 human hepatocellular carcinoma cell line as a negative control (right) using RIPK/RIP3 Antibody (1312D) (NBP2-76799). Cells were stained using the NorthernLights 557-conjugated Anti-Rabbit IgG Secondary Antibody (red; NL004) and counterstained with DAPI (NBP2-31156) (blue).
The nature of pathogen and the host tissue determines whether RIPK3 would be beneficial for the host or not. RIPK3-deficient animals develop normally but are susceptible to certain viruses. In RIPK3-deficient settings, the necrosome may trigger caspase-8-dependent apoptosis, rather than necroptosis. It is unclear if RIPK3-mediated viral clearance is because of caspase-independent necroptosis, some transcriptional responses such as caspase-8-dependent apoptosis, or both.1,3
RIPK3 and RHIM signaling can protect host cells against some bacteria. Enteropathogenic Escherichia coli and a similar pathogen Citrobacter rodentium were found to release certain proteases that cleave RHIM domain to infect and damage the host intestinal cells. Staphylococcus aureus activates RIPK3-mediated necroptosis, which eliminates infected skin cells. However, the RIPK3-dependent necroptosis of macrophages caused by Salmonella enterica serovar Typhimurium as well as Mycobacterium tuberculosis leads to the spread of these pathogens. Likewise, acute or chronic injuries such as ischemia can also lead to RIPK3-dependent necroptosis and tissue damage.3
Overall, RIPK3-mediated protection may come at a cost of host tissue damage.
Immunohistochemical staining of mouse kidney tissue embedded in paraffin using Rabbit Polyclonal RIPK3/RIP3 Antibody (NBP1-77299) at a concentration of 2.5µg/mL.
The researchers in the USA, UK and France recently achieved a milestone in understanding the immunogenicity of necroptotic cells.4 They discovered that when a cell is irreversibly committed to necroptosis and has lost its cell membrane integrity, the mRNA translation in the necroptotic corpses continues to produce cytokines including IL-6, CXCL1, CXCL2 and CCL2. This facilitates activation of innate immune cells and primes the adaptive immune responses against the antigens associated with necroptotic cells.4
Researchers at the University Hospital Schleswig-Holstein, Germany, used necroptosis-sensitive cell lines and transgenic mice to discover that Ripk3-deficient mice are protected against kidney ischemia reperfusion injury and TNF-induced toxicity.5 Interestingly, the extent of protection against these necroptosis-mediated pathologies was similar to that of Mlkl- or Ripk3-Mlkl double deficient mice.
In short, RIPK3 activation defines necroptosis. RIPK3 can be a protector against inflammation and pathology, but it can also lead to tissue injury.
Note:
Orozco et al. (2019) used Anti-RIPK3 (NBP1-77299).
Moerke et al. (2019) used Recombinant carrier-free murine TNF&alpha and Erastin and 1S,3R-RSL3 .
Jamshed Arslan, Pharm D, PhD
Dr Arslan is an Assistant Professor at Barrett Hodgson University, Pakistan,
where he uses various pedagogical methods to teach Pharm D students.
Research in focus
