| First Author | Khanna K | Year | 2024 |
| Journal | Arthritis Rheumatol | Volume | 76 |
| Issue | 1 | Pages | 107-118 |
| PubMed ID | 37534578 | Mgi Jnum | J:350050 |
| Mgi Id | MGI:7619171 | Doi | 10.1002/art.42666 |
| Citation | Khanna K, et al. (2024) Tmem178 Negatively Regulates IL-1beta Production Through Inhibition of the NLRP3 Inflammasome. Arthritis Rheumatol 76(1):107-118 |
| abstractText | OBJECTIVE: Inflammasomes modulate the release of bioactive interleukin (IL)-1beta. Excessive IL-1beta levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1beta regulation in these disorders. METHODS: To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Transmembrane protein 178 (Tmem178), a negative regulator of calcium levels in macrophages, and measured IL-1beta and caspase-1 activation in wild-type (WT) and Tmem178(-/-) macrophages after calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking the Stromal Interaction Molecule 1 (Stim1) binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin(-/-) /Tmem178(-/-) mice infected with lymphocytic choriomeningitis virus (LCMV) in which inflammasome or IL-1beta signaling was pharmacologically inhibited. Human TMEM178 and IL1B transcripts were analyzed in data sets of whole blood and peripheral blood monocytes from healthy controls and patients with active sJIA. RESULTS: TMEM178 levels are reduced in whole blood and monocytes from patients with sJIA while IL1B levels are increased. Accordingly, Tmem178(-/-) macrophages produce elevated IL-1beta compared with WT cells. The elevated intracellular calcium levels after SOCE activation in Tmem178(-/-) macrophages induce mitochondrial damage, release mtROS, and ultimately promote NLRP3 inflammasome activation. In vivo, inhibition of inflammasome or IL-1beta neutralization prolongs Tmem178(-/-) mouse survival in LCMV-induced CSS. CONCLUSION: Down-regulation of TMEM178 levels may represent a marker of disease activity and help identify patients who could benefit from inflammasome targeting. |
