Many infectious and inflammatory diseases, including malaria or coronavirus infections and sickle cell disease, cause red blood cells to rupture and leak their contents. mostly hemoglobin. In the bloodstream, hemoglobin breaks down releasing the heme cofactor group. The above conditions, which can include hemorrhagic stroke, can cause red blood cells to break down, a process called hemolysis. Free heme can cause significant inflammation and organ damage, leading to morbidity and mortality. Researchers at St. Jude Children’s Research Hospital have discovered that NLRP12, an innate immune pattern recognition receptor, is the key molecule responsible for inducing inflammatory cell death and pathology in response to heme combined with other cellular damage or infections.
Scientists have known for decades that hemolysis leads to organ damage, but the mechanism behind the disease’s pathology was unclear. The NLR family contains proteins that have been known to be important in disease for years, but what many of these proteins respond to for activation and how this affects disease has remained a mystery. As an example, it took 20 years of research into the trigger of NLRP12 and the specific signaling pathway it activated, to discover that heme, combined with specific components of cell injury or infection, can activate NLRP12 to drive the death and pathology of inflammatory cells in disease. The St. Jude group demonstrated that NLRP12 was the crucial innate immune molecule driving the heme-induced inflammatory cell death response.
But heme alone was not sufficient to induce NLRP12 expression and initiate the subsequent cell death process. Another simultaneous component, such as from an infection (a pathogen-associated molecular pattern or PAMP) or cell damage such as cytokine release, was also required to trigger NLRP12 production and cell death. Two types of signals enter the cell and thus NLRP12 engages many other proteins as an organizer to drive cell death. The researchers demonstrated that NLRP12 recruits these other molecules to create a PANoptosome, a complex that induces a form of innate immune inflammatory cell death called PANoptosis. The PANoptosome contains many proteins, including the inflammasome and specific components caspase-8 and RIPK3 that drive cell death.
Excessive activation of PANoptosis is known to lead to inflammatory diseases. Thus, NLRP12 is a direct bridge from hemolysis to inflammatory disease. The researchers also found that NLRP12 was highly expressed in patients with various diseases, including traditionally haemolytic diseases, such as sickle cell disease and malaria, and infections, such as SARS-CoV-2, influenza and bacterial pneumonia. When the researchers knocked out the Nlrp12 gene in mice, they no longer succumbed to organ damage in a model of hemolytic disease. Together, the results showed that NLRP12-mediated PANoptosis is a key factor in morbidity and mortality. These findings have important implications not only in hemolytic disease but also in infections and other conditions in which hemolysis occurs.
Research has linked genetic mutations in NLRP12 to several diseases. Previous studies have also demonstrated that cell death, characterized by the activation of necroptotic and apoptotic molecules, can be induced by heme more potent cytokines such as TNF-alpha. This is exactly what happens for the activation of NLRP12. Excess circulating TNF-alpha is a feature of both infectious and inflammatory diseases, suggesting that NLRP12 may play a role in heme-mediated cell death in both infections and inflammatory diseases. Now that the regulation and function of NLRP12 in inflammatory cell death have been identified in this study, potential drugs can be designed to prevent cell death in inflammatory diseases in which the PANoptosome is involved.
In addition to inflammatory bowel disease or autoimmune conditions such as lupus or scleroderma, this information may apply more specifically to hemorrhagic brain stroke. At this juncture, just think that stroke currently affects more than 800,000 Europeans every year. In 20% of cases it is of the hemorrhagic type and fatal in 70% within a few weeks.
By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
Sundaram B, Pandian N, Mall R et al. Cell 2023 May 29: in press.
Sundaram B et al. Immunohorizons. 2022 Mar 17; 6(3):243-252.
Wang Y, Pandian N, Han JH et al. Mol Life Sci. 2022; 79(10):531.
Christgen S et al. Front Cell Infect Microbiol. 2020 May 29; 10:237.