Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Abstract

Background Approximately 8–9% of the world’s population is affected by autoimmune diseases, and yet the mechanism of autoimmunity trigger is largely understudied. Two unique cell death modalities, ferroptosis and pyroptosis, provide a new perspective on the mechanisms leading to autoimmune diseases, and development of new treatment strategies. Methods Using scRNA-seq datasets, the aberrant trend of ferroptosis and pyroptosis-related genes were analyzed in several representative autoimmune diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and experimental autoimmune orchitis). Cell line models were also assessed using bulk RNA-seq and qPCR. Results A substantial difference was observed between normal and autoimmune disease samples involving ferroptosis and pyroptosis. In the present study, ferroptosis and pyroptosis showed an imbalance in different keratinocyte lineages of psoriatic skinin addition to a unique pyroptosis-sensitive keratinocyte subset in atopic dermatitis (AD) skin. The results also revealed that pyroptosis and ferroptosis are involved in epidermal melanocyte destruction in vitiligo. Aberrant ferroptosis has been detected in multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and autoimmune orchitis. Cell line models adopted in the study also identified pro-inflammatory factors that can drive changes in ferroptosis and pyroptosis. Conclusion These results provide a unique perspective on the involvement of ferroptosis and pyroptosis in the pathological process of autoimmune diseases at the scRNA-seq level. IFN-γ is a critical inducer of pyroptosis sensitivity, and has been identified in two cell line models.

Association of COVID-19 mortality with serum selenium, zinc and copper: Six observational studies across Europe

“…The understanding of the molecular effects of Se deficiency and supplemental Se intake on the immune system is more solid, as the Se status directly affects the expression of selenoproteins relevant to the immune system ( 62 – 64 ). The link extents to multiple levels, including quality control of newly synthesized proteins in the ER to prevent secretion of immunogenic misfolded proteins ( 65 , 66 ), a direct involvement of selenoproteins in intracellular lymphocyte signaling ( 67 – 69 ), and an effect of selenoproteins, particularly GPX4, on immune cell survival and protection against hyperactivation–induced ferroptosis ( 70 , 71 ). Given that severe Se deficiency is an established risk factor for autoimmune disease ( 72 – 74 ) and appears to influence mortality risk in critical illness ( 20 , 75 , 76 ), the consistent associations observed in this study support discussion of active supplementation of COVID-19 patients with severe deficiency to achieve reference concentrations ( 19 ).…”

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

“…Furthermore, non-canonical (involving caspase 4/5) NLRP3 inflammasome activation, also leading to canonical NLRP3 inflammasome activation, appears unique for MIS-C [ 8 ]. If uninhibited, aberrant activation of pyroptosis leads to massive DAMPs release, able to amplify and perpetuate uncontrolled inflammatory immune responses, potentially leading to autoantibody formation and autoimmunity [ 24 ]. Stringent host regulation of NLRP3 inflammasome activation is necessary, to avoid detrimental inflammatory reactions, as seen in numerous autoinflammatory and autoimmune diseases [ 18 , 19 , 24 ].…”

“…If uninhibited, aberrant activation of pyroptosis leads to massive DAMPs release, able to amplify and perpetuate uncontrolled inflammatory immune responses, potentially leading to autoantibody formation and autoimmunity [ 24 ]. Stringent host regulation of NLRP3 inflammasome activation is necessary, to avoid detrimental inflammatory reactions, as seen in numerous autoinflammatory and autoimmune diseases [ 18 , 19 , 24 ]. Thus, loss of control of inflammasome regulation in genetically predisposed children, could potentially pave the way towards MIS-C [ 22 , 25 ].…”

Identification of Key Ferroptosis-Related Genes in the Peripheral Blood of Patients with Relapsing-Remitting Multiple Sclerosis and Its Diagnostic Value

“…The iron homeostasis in the brain of MS patients is severely disrupted, resulting from iron overload in lesional myeloid cells and deep nuclei, as well as decreased iron concentration in normal white matter and chronic cortical lesions [ 10 ]. A recent single-cell sequencing analysis of brain cells isolated from MS patients showed that the expression levels of some important anti-ferroptosis genes in neurons and oligodendrocytes were lower than those in normal individuals [ 11 ]. GPX4 , a gene that plays a significant role in anti-ferroptosis, was found to be down-regulated in some cell types of MS patients [ 11 ].…”

“…A recent single-cell sequencing analysis of brain cells isolated from MS patients showed that the expression levels of some important anti-ferroptosis genes in neurons and oligodendrocytes were lower than those in normal individuals [ 11 ]. GPX4 , a gene that plays a significant role in anti-ferroptosis, was found to be down-regulated in some cell types of MS patients [ 11 ]. This was also confirmed in a previous study by Hu et al, which showed that GPX4 expression was generally reduced in the gray matter of MS and the spinal cord of experimental autoimmune encephalomyelitis (EAE) [ 12 ], the most commonly used experimental model for MS [ 13 ].…”